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Rogers MC, Ash M, Hernandez A, Hosler GA. A Patient With Concurrent Hidradenitis Suppurativa and Porokeratosis Palmaris et Plantaris Disseminata: Case Report and Review of Autoinflammatory Keratinization Diseases. J Cutan Pathol 2025; 52:272-277. [PMID: 39749894 PMCID: PMC11885075 DOI: 10.1111/cup.14774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 11/18/2024] [Accepted: 11/26/2024] [Indexed: 01/04/2025]
Abstract
The term autoinflammatory keratinization diseases (AIKDs) was recently proposed as a unifying concept for diseases characterized by inflammation in the epidermis and upper dermis which leads to hyperkeratosis, caused by genetic perturbations of the innate immune system. We present a case of a patient with hidradenitis suppurativa and porokeratosis, two AIKDs, followed by a review of these conditions as well as other AIKDs. This case was distinguished by hypertrophic porokeratoses involving cystic hair follicles, showing histopathologic features of both conditions within single biopsy specimens. The patient's course was additionally complicated by SCC arising within a porokeratosis. Our case demonstrates a rare overlap of two AIKDs, occurring not only within the same patient but also within the same lesions.
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Affiliation(s)
- Meredith C. Rogers
- Department of DermatologyUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Mark Ash
- Empire DermatologySyracuseNew YorkUSA
| | | | - Gregory A. Hosler
- Department of DermatologyUniversity of Texas Southwestern Medical CenterDallasTexasUSA
- ProPathDallasTexasUSA
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2
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Natsuga K. Advanced phasing techniques in congenital skin diseases. J Dermatol 2025; 52:392-399. [PMID: 39723554 PMCID: PMC11883850 DOI: 10.1111/1346-8138.17597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/26/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024]
Abstract
Phasing, the process of determining which alleles at different loci on homologous chromosomes belong together on the same chromosome, is crucial in the diagnosis and management of autosomal recessive diseases. Advances in long-read sequencing technologies have significantly enhanced our ability to accurately determine haplotypes. This review discusses the application of low-coverage long-read sequencing, nanopore Cas9-guided long-read sequencing, and adaptive sampling in phasing, highlighting their utility in complex clinical scenarios. Through clinical vignettes, we explore the importance of phasing in gene therapy design for recessive dystrophic epidermolysis bullosa and the role of revertant mosaicism in therapeutic epidermal autografts. Despite its promise, phasing with long-read sequencing faces challenges, including low efficiency in enriching target regions and the inherent error rate of nanopore sequencing. Future developments in long-read sequencing technologies will be critical in overcoming these limitations and expanding the applicability of phasing across various clinical settings.
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Affiliation(s)
- Ken Natsuga
- Department of Dermatology, Faculty of Medicine and Graduate School of MedicineHokkaido UniversitySapporoJapan
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3
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Kostopoulos‐Kanitakis K, Kanitakis J. Porokeratoses: an update on pathogenesis and treatment. Int J Dermatol 2025; 64:62-71. [PMID: 39129190 PMCID: PMC11685060 DOI: 10.1111/ijd.17411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 07/05/2024] [Accepted: 07/08/2024] [Indexed: 08/13/2024]
Abstract
Porokeratoses (PK) are a group of uncommon dermatoses characterized by abnormal epidermal differentiation due to a disorder of the mevalonate metabolic pathway. Several clinical subtypes exist that can be associated with the same patient or affect different patients within a family and could, therefore, be different expressions of one disease. All PK subtypes share a common histopathologic finding, the cornoid lamella, a vertical stack of parakeratotic corneocytes embedded in an orthokeratotic horny layer. PK often affects immunosuppressed patients, in whom the course may parallel the level of immunosuppression. The pathogenesis of PK, which had long remained mysterious, has been recently unraveled after discovering pathogenic variants of genes involved in the mevalonate metabolic pathway. The disease is due to germline pathogenic variants of genes of this pathway but requires a second-hit event to manifest; therefore, PK is considered a dominantly inherited but recessively expressed condition. The prognosis of PK is usually favorable, even though the lesions progress to keratinocyte carcinomas in 7%-16% of patients. The treatment of PK was based on physical (ablative) procedures and various (topical or systemic) treatments, whose efficacy is nevertheless inconsistent and often temporary. The discovery of the metabolic pathway involved in the pathogenesis of PK paved the way for the elaboration of new topical treatments (combination of statins and cholesterol), which are more regularly efficacious compared with older treatments, even though the management of some patients with PK may still be challenging.
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Affiliation(s)
| | - Jean Kanitakis
- Department of DermatologyEdouard Herriot HospitalLyonFrance
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4
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Wu X, Li L, Lu Z, Hu X, Lu Y, Liu Y, Xu G, Ding Q, Wang X, Wu W, Jin P, Dai J. Heterozygous Prothrombin Mutation-Associated Thrombophilia. Thromb Haemost 2025; 125:69-81. [PMID: 38914130 DOI: 10.1055/a-2350-8338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
BACKGROUND Venous thromboembolism (VTE) is predisposed by thrombotic mutations in patients with hereditary thrombophilia. Although prothrombin deficiencies caused by homozygous or compound heterozygous mutations are associated with bleeding diathesis, rare cases have shown a correlation between heterozygous prothrombin mutations and thrombosis. MATERIALS AND METHODS We surveyed genetic variants involved in thrombosis and hemostasis in 347 patients with unprovoked VTE or having a positive family history of thrombosis. For patients identified with heterozygous prothrombin mutations, we conducted family investigations and performed a thrombin generation test (TGT) to elucidate the thrombotic risk. Novel mutants were expressed and subjected to functional assays to clarify the underlying thrombotic mechanisms. RESULTS Heterozygous prothrombin mutations were identified in 3.5% of patients (12/347), including three novel mutations Phe382Ser, Phe382Leu, and Asp597Tyr found in one patient each, as well as previously reported Arg541Trp mutation in four patients and Arg596Gln mutation in five patients. A total of 42 mutation carriers were identified within the 12 pedigrees, among whom 64.3% (27/42) had experienced thrombotic events. TGT results demonstrated hypercoagulability for carriers of the five mutations, with Arg596Gln showing the highest thrombin generation potential followed by Arg541Trp. The Phe382-associated mutations severely impaired thrombomodulin-binding ability of thrombin, resulting in obviously reduced protein C (PC) activation. The Asp597Tyr mutation exhibited a mild reduction in both inactivation by antithrombin and PC activation reactions. CONCLUSION The presence of heterozygous prothrombin mutations represents a potential genetic predisposition for VTE. All thrombosis-associated mutations potentiate coagulation activity by either conferring antithrombin resistance and/or impairing PC pathway activity.
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Affiliation(s)
- Xi Wu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Li
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhengjing Lu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaobo Hu
- Shanghai Center for Clinical Laboratory, Shanghai, China
| | - Yeling Lu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Liu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guanqun Xu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qiulan Ding
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuefeng Wang
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Laboratory Medicine, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Collaborative Innovation Center of Hematology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenman Wu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Laboratory Medicine, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Collaborative Innovation Center of Hematology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peipei Jin
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Dai
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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5
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Wu Y, Gao X, Yu Q, Shi J, Xu Y, Chen J. A Case of Palmoplantar Porokeratosis With Hypokeratosis: A New Subtype of Porokeratosis? Am J Dermatopathol 2024; 46:887-889. [PMID: 38842349 DOI: 10.1097/dad.0000000000002641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2024]
Affiliation(s)
- Yichen Wu
- Department of Rheumatology and Immunology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoyan Gao
- Department of Dermatology, Changxing Skin Disease Hospital, Zhejiang, China
| | - Qi Yu
- Department of Dermatopathology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
| | - Juan Shi
- Department of Rheumatology and Immunology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yueming Xu
- Department of Dermatology, Changxing Skin Disease Hospital, Zhejiang, China
| | - Jia Chen
- Department of Rheumatology and Immunology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China
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Tognetti L, Cappilli S, Falcinelli F, Soglia S, Lacarrubba F, Maione V, Ricci C, Suppa M, Venturini M, Cinotti E, Di Stefani A, Perrot JL, Rubegni P. Line-field confocal optical coherence tomography for the differential diagnosis of porokeratosis from clinical mimickers: a preliminary study. Clin Exp Dermatol 2024; 49:1641-1650. [PMID: 39056248 DOI: 10.1093/ced/llae285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 05/15/2024] [Accepted: 07/08/2024] [Indexed: 07/28/2024]
Abstract
BACKGROUND Porokeratosis variants are relatively rare and can be clinically misdiagnosed with several common papulokeratotic mimickers. Line-field confocal optical coherence tomography (LC-OCT) is a new technology able to explore the skin in vivo up to a depth of 500 µm. OBJECTIVES To investigate the role of LC-OCT in the diagnosis of many porokeratosis variants in a preliminary study. METHOD In total, 130 LC-OCT images were obtained from 98 patients, 45 affected by a porokeratosis variant (69 images) and 53 with a mimicker condition (61 images). RESULTS We found almost perfect interobserver agreement for LC-OCT image interpretation and perfect correspondence with the findings from histological slides. In addition, a series of morphological in vivo and three-dimensional features related to the cornoid lamella were detected by LC-OCT that were not visible from the histology. CONCLUSIONS This device can be proposed to assist with rapid bedside noninvasive differentiation of porokeratosis variants from their mimickers, possibly sparing incisional biopsy in patients where the diagnosis is uncertain.
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Affiliation(s)
- Linda Tognetti
- Dermatology Unit and Skin Bank, Department of Medical, Surgical and Neurosciences, Siena University Hospital, Siena, Italy
| | - Simone Cappilli
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome,Italy
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Falcinelli
- Dermatology Unit and Skin Bank, Department of Medical, Surgical and Neurosciences, Siena University Hospital, Siena, Italy
| | - Simone Soglia
- Department of Dermatology, University of Brescia, Brescia, Italy
| | | | - Vincenzo Maione
- Department of Dermatology, University of Brescia, Brescia, Italy
| | - Costantino Ricci
- Unit of Pathology, Maggiore Hospital, AUSL Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Mariano Suppa
- Department of Dermatology, Hôpital Erasme, HUB, Université Libre de Bruxelles, Belgium
- Department of Dermatology, Institut Jules Bordet, HUB, Université Libre de Bruxelles, HUB, Brussels, Belgium
- Groupe d'imagerie cutanée noninvasive (GICNI) of the Société Française de Dermatologie (SFD), Paris, France
| | - Marina Venturini
- Department of Dermatology, University of Brescia, Brescia, Italy
| | - Elisa Cinotti
- Dermatology Unit and Skin Bank, Department of Medical, Surgical and Neurosciences, Siena University Hospital, Siena, Italy
- Groupe d'imagerie cutanée noninvasive (GICNI) of the Société Française de Dermatologie (SFD), Paris, France
| | - Alessandro Di Stefani
- UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome,Italy
- Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Jean Luc Perrot
- Groupe d'imagerie cutanée noninvasive (GICNI) of the Société Française de Dermatologie (SFD), Paris, France
- Department of Dermatology, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Pietro Rubegni
- Dermatology Unit and Skin Bank, Department of Medical, Surgical and Neurosciences, Siena University Hospital, Siena, Italy
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Lengvári L, Takács K, Lengyel A, Pálinkás A, Wouters CH, Koné-Paut I, Kuemmerle-Deschner J, Jeyaratnam J, Anton J, Lachmann HJ, Gattorno M, Hofer M, Toplak N, Weiser P, Kallinich T, Ozen S, Hentgen V, Uziel Y, Horváth Z, Szabados M, Brogan P, Constantin T, Frenkel J. Mevalonate kinase deficiency: an updated clinical overview and revision of the SHARE recommendations. Front Immunol 2024; 15:1466844. [PMID: 39600705 PMCID: PMC11590122 DOI: 10.3389/fimmu.2024.1466844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 10/09/2024] [Indexed: 11/29/2024] Open
Abstract
Mevalonate kinase deficiency (MKD), a rare auto-inflammatory disorder, arises from mutations in the MVK gene, disrupting isoprenoid biosynthesis, and affecting cellular processes. This comprehensive review provides an updated perspective on MKD, including its aetiology, pathogenesis, diagnostic modalities, and therapeutic strategies. Based on recent research and clinical advances, our objective is to bridge the knowledge gaps in the 2015 SHARE guidelines. By describing molecular mechanisms, diagnostic dilemmas, and emerging therapies, this article should serve as a resource for clinicians and researchers, promoting a deeper understanding of MKD and guiding optimal patient care.
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Affiliation(s)
- Lilla Lengvári
- Paediatric Centre, Semmelweis University, Budapest, Hungary
| | - Kata Takács
- Paediatric Centre, Semmelweis University, Budapest, Hungary
| | - Anna Lengyel
- Paediatric Centre, Semmelweis University, Budapest, Hungary
| | | | | | - Isabelle Koné-Paut
- Department of Pediatric Rheumatology, National Reference Centre for Rare Autoinflammatory Diseases and Inflammatory Amyloidosis, Centre Hospitalier Universitaire de Bicêtre, Assistance Publique-Hôpitaux de Paris, University of Paris Saclay, Le Kremlin-Bicêtre, France
| | - Jasmin Kuemmerle-Deschner
- Pediatric Rheumatology, Department of Pediatrics and Autoinflammation Reference Center, University Hospital Tuebingen, Tuebingen, Germany
| | - Jerold Jeyaratnam
- Division of Woman and Infant, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, Netherlands
| | - Jordi Anton
- Department of Pediatric Rheumatology, Hospital Sant Joan de De´ u, University of Barcelona, Barcelona, Spain
| | - Helen Jane Lachmann
- National Amyloidosis Centre, University College London, and Royal Free Hospital London NHS Foundation Trust, London, United Kingdom
| | - Marco Gattorno
- UOC Reumatologia e Malattie Autoinfiammatorie, IRCCS Istituto G. Gaslini, Genoa, Italy
| | - Michael Hofer
- Pediatric Rheumatology and Immunology, Hoˆ pital Riviera-Chablais, Rennaz, Switzerland
| | - Nataša Toplak
- Department of Allergology, Rheumatology and Clinical Immunology, University Children’s Hospital Ljubljana, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Peter Weiser
- Division of Rheumatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Tilmann Kallinich
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charite´ – Universitätsmedizin Berlin, Berlin, Germany
| | - Seza Ozen
- Department of Pediatric Rheumatology, Hacettepe University, Ankara, Türkiye
| | - Véronique Hentgen
- French Reference Center for AutoInflammatory Diseases and Amyloidosis, Department of Pediatrics, Versailles Hospital, Versailles, France
| | - Yosef Uziel
- Pediatric Rheumatology Unit, Meir Medical Center, Tel Aviv University School of Medicine, Tel Aviv, Israel
| | | | | | - Paul Brogan
- Inflammation & Rheumatology Section, UCL Great Ormond St Institute of Child Health, University College London, London, United Kingdom
| | | | - Joost Frenkel
- Division of Pediatrics, Wilhelmina Children’s Hospital University Medical Center Utrecht, Utrecht, Netherlands
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8
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Peng K, Wong W, Yan K, Zhang Z. Effective treatment of solar facial porokeratosis in one patient with topical atorvastatin/cholesterol cream. Clin Exp Dermatol 2024; 49:1239-1241. [PMID: 38680042 DOI: 10.1093/ced/llae156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 03/17/2024] [Accepted: 05/14/2024] [Indexed: 05/01/2024]
Abstract
We report a rare case of solar facial porokeratosis (SFP) treated topically with atorvastatin/cholesterol or cholesterol alone for 48 weeks. The patient reported no obvious skin irritation and was delighted with the outcome. This study supported the effectiveness of a pathogenesis-directed treatment for SFP. Moreover, we point out that topical statins combined with cholesterol might have a long-term benefit in the treatment of SFP.
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Affiliation(s)
- Kexin Peng
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, People's Republic of China
| | - Wenghong Wong
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, People's Republic of China
| | - Kexiang Yan
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, People's Republic of China
| | - Zhenghua Zhang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, People's Republic of China
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9
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Yu T, Yin Y, Shu C, Yuan CD. MVD Variants Identified in a Rare Clinical Variant of Porokeratosis: A Case Report of Disseminated Superficial Porokeratosis (DSP) in a Chinese Patient. Clin Cosmet Investig Dermatol 2024; 17:1783-1787. [PMID: 39132030 PMCID: PMC11313490 DOI: 10.2147/ccid.s473076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 07/14/2024] [Indexed: 08/13/2024]
Abstract
Porokeratosis comprises a diverse range of both hereditary and acquired disorders characterized by clonal hyperproliferation of keratinocytes. These disorders manifest with a variety of clinical presentations but are histologically unified by the presence of the cornoid lamella. In this study, we report an unusual presentation of a rare clinical variant of porokeratosis, namely disseminated superficial porokeratosis, in which mutations in the Mevalonate decarboxylase (MVD) gene have been identified. This finding contributes to the growing understanding of the genetic underpinnings of this complex dermatological condition and may have implications for diagnosis and treatment.
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Affiliation(s)
- Tao Yu
- Department of Dermatology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Yue Yin
- Department of Dermatology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Chang Shu
- Department of Pathology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Cheng-da Yuan
- Department of Dermatology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
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10
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La Y, Zhu J, Mueller SM. Conventional and Novel Treatment Strategies for Porokeratoses: A Narrative Review. J Dtsch Dermatol Ges 2024; 22:1073-1077. [PMID: 38961534 DOI: 10.1111/ddg.15436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/25/2024] [Indexed: 07/05/2024]
Abstract
Porokeratoses are a heterogenous group of autoinflammatory keratinization disorders all characterized by the presence of a cornoid lamella. In addition to gene mutations affecting the mevalonate pathway, environmental factors such as UV radiation, immunosuppression, trauma, and infection are also thought to contribute to porokeratoses. To date, there are no management guidelines or levels of evidence for commonly used pharmacologic and non-pharmacologic treatment options for porokeratoses. Conventional treatment strategies encompass topical and systemic drugs (e.g., salicylic acid, topical glucocorticoids, and retinoids), phototherapy, laser, and surgical interventions. Better insights into the pathogenesis of porokeratoses have paved the way for the development of novel therapeutic approaches, such as topical statins or the use of monoclonal antibodies. This narrative review aims to summarize both conventional and novel treatment options, including their level of evidence, advantages, and disadvantages.
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Affiliation(s)
- Yumeng La
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, China
| | - Jie Zhu
- Department of Dermatology, University Hospital Basel, Basel, Switzerland
| | - Simon M Mueller
- Department of Dermatology, University Hospital Basel, Basel, Switzerland
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11
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La Y, Zhu J, Mueller SM. Konventionelle und neue Behandlungsstrategien bei Porokeratosen: Eine narrative Übersicht. J Dtsch Dermatol Ges 2024; 22:1073-1078. [PMID: 39105229 DOI: 10.1111/ddg.15436_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/25/2024] [Indexed: 08/07/2024]
Abstract
ZusammenfassungPorokeratosen sind eine heterogene Gruppe autoinflammatorischer Keratinisierungsstörungen, die durch kornoide Lamellen gekennzeichnet sind. Neben Genmutationen, die sich auf den Mevalonat‐Stoffwechselweg auswirken, werden auch Umweltfaktoren wie UV‐Strahlung, Immunsuppression, Traumata und Infektionen für die Entstehung von Porokeratosen verantwortlich gemacht. Bislang gibt es keine Behandlungsrichtlinien oder Evidenzgrade für die gängigen pharmakologischen und nicht‐pharmakologischen Behandlungsoptionen bei Porokeratosen. Zu den konventionellen Behandlungen zählen topische und systemische Medikamente wie Salicylsäure, topische Glucocorticoide und Retinoide, Phototherapie, Laser und chirurgische Verfahren. Bessere Erkenntnisse über die Pathogenese von Porokeratosen haben die Entwicklung neuartiger therapeutischer Ansätze ermöglicht, etwa topische Statine oder monoklonale Antikörper. In dieser narrativen Übersichtsarbeit werden sowohl die herkömmlichen als auch neuen Behandlungsmöglichkeiten einschließlich ihres Evidenzgrads sowie ihrer Vor‐ und Nachteile zusammengefasst.
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Affiliation(s)
- Yumeng La
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, China
| | - Jie Zhu
- Department of Dermatology, University Hospital Basel, Basel, Switzerland
| | - Simon M Mueller
- Department of Dermatology, University Hospital Basel, Basel, Switzerland
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12
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Woźna J, Korecka K, Bowszyc-Dmochowska M, Jałowska M. Porokeratosis of Mibelli Treated With Topical 2% Lovastatin/2% Cholesterol Ointment. Cureus 2024; 16:e65871. [PMID: 39219867 PMCID: PMC11364359 DOI: 10.7759/cureus.65871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
Porokeratosis is characterized by disruptions in the isoprenoid pathway, leading to the development of cornoid lamella, a unique skin lesion consisting of parakeratotic cells. The condition has a genetic foundation involving mutations affecting cholesterol synthesis, and new treatments aim to address these metabolic disruptions. This study examines a 56-year-old male with porokeratosis of Mibelli (PM) who presented with a non-healing erosion on his finger that persisted for two years. Previous therapies, including corticosteroids, antibiotics, and tacrolimus, proved ineffective. The patient then received a novel treatment with a topical 2% lovastatin/2% cholesterol ointment. After nine months, there was significant clinical improvement; the lesion was markedly reduced in size and appearance. This case underscores the potential of lovastatin/cholesterol ointment as an effective treatment for PM, indicating its promise for broader therapeutic applications.
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Affiliation(s)
- Julia Woźna
- Department of Dermatology, Poznan University of Medical Sciences, Poznan, POL
| | - Katarzyna Korecka
- Department of Dermatology and Venereology, Poznan University of Medical Sciences, Poznan, POL
| | - Monika Bowszyc-Dmochowska
- Department of Dermatology, Cutaneous Histopathology and Immunopathology Section, Poznan University of Medical Sciences, Poznan, POL
| | - Magdalena Jałowska
- Department of Dermatology, Poznan University of Medical Sciences, Poznan, POL
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13
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Randén-Brady R, Carpén T, Hautala LC, Tolvanen T, Haglund C, Joenväärä S, Mattila P, Mäkitie A, Lehtonen S, Hagström J, Silén S. LRG1 and SDR16C5 protein expressions differ according to HPV status in oropharyngeal squamous cell carcinoma. Sci Rep 2024; 14:14148. [PMID: 38898137 PMCID: PMC11187215 DOI: 10.1038/s41598-024-64823-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 06/13/2024] [Indexed: 06/21/2024] Open
Abstract
The increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) is primarily due to human papillomavirus, and understanding the tumor biology caused by the virus is crucial. Our goal was to investigate the proteins present in the serum of patients with OPSCC, which were not previously studied in OPSCC tissue. We examined the difference in expression of these proteins between HPV-positive and -negative tumors and their correlation with clinicopathological parameters and patient survival. The study included 157 formalin-fixed, paraffin-embedded tissue samples and clinicopathological data. Based on the protein levels in the sera of OPSCC patients, we selected 12 proteins and studied their expression in HPV-negative and HPV-positive OPSCC cell lines. LRG1, SDR16C5, PIP4K2C and MVD proteins were selected for immunohistochemical analysis in HPV-positive and -negative OPSCC tissue samples. These protein´s expression levels were compared with clinicopathological parameters and patient survival to investigate their clinical relevance. LRG1 expression was strong in HPV-negative whereas SDR16C5 expression was strong in HPV-positive tumors. Correlation was observed between LRG1, SDR16C5, and PIP4K2C expression and patient survival. High expression of PIP4K2C was found to be an independent prognostic factor for overall survival and expression correlated with HPV-positive tumor status. The data suggest the possible role of LRG1, SDR16C5 and PIP4K2C in OPSCC biology.
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Affiliation(s)
- Reija Randén-Brady
- Department of Pathology, University of Helsinki, 00014, Helsinki, Finland.
- Department of Pathology, University of Helsinki and Helsinki University Hospital, 00290, Helsinki, Finland.
| | - Timo Carpén
- Department of Pathology, University of Helsinki, 00014, Helsinki, Finland
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki, and Helsinki University Hospital, 00029, Helsinki, Finland
- Faculty of Medicine, Research Program in Systems Oncology, University of Helsinki, 00014, Helsinki, Finland
| | - Laura C Hautala
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, 00014, Helsinki, Finland
| | - Tuomas Tolvanen
- Department of Pathology, University of Helsinki, 00014, Helsinki, Finland
| | - Caj Haglund
- University of Helsinki, and Helsinki University Hospital, 00029, Helsinki, Finland
| | - Sakari Joenväärä
- Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Hospital, 00029, Helsinki, Finland
- HUS Diagnostic Center, Department of Pathology, HUSLAB, Helsinki University Hospital, 00029, Helsinki, Finland
| | - Petri Mattila
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki, and Helsinki University Hospital, 00029, Helsinki, Finland
| | - Antti Mäkitie
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki, and Helsinki University Hospital, 00029, Helsinki, Finland
- Faculty of Medicine, Research Program in Systems Oncology, University of Helsinki, 00014, Helsinki, Finland
- Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institute and Karolinska Hospital, 171 76, Stockholm, Sweden
| | - Sanna Lehtonen
- Department of Pathology, University of Helsinki, 00014, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, 00014, Helsinki, Finland
| | - Jaana Hagström
- Department of Pathology, University of Helsinki, 00014, Helsinki, Finland
- Research Programs Unit, Translational Cancer Medicine, University of Helsinki, 00014, Helsinki, Finland
- Department of Oral Pathology and Oral Radiology, University of Turku, 20520, Turku, Finland
- Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Hospital, 00029, Helsinki, Finland
- HUS Diagnostic Center, Department of Pathology, HUSLAB, Helsinki University Hospital, 00029, Helsinki, Finland
| | - Suvi Silén
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki, and Helsinki University Hospital, 00029, Helsinki, Finland
- Faculty of Medicine, Research Program in Systems Oncology, University of Helsinki, 00014, Helsinki, Finland
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14
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Saito S, Saito Y, Sato S, Aoki S, Fujita H, Ito Y, Ono N, Funakoshi T, Kawai T, Suzuki H, Sasaki T, Tanaka T, Inoie M, Hata K, Kataoka K, Kosaki K, Amagai M, Nakabayashi K, Kubo A. Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis. Am J Hum Genet 2024; 111:896-912. [PMID: 38653249 PMCID: PMC11080608 DOI: 10.1016/j.ajhg.2024.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/12/2024] [Accepted: 03/28/2024] [Indexed: 04/25/2024] Open
Abstract
Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.
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Affiliation(s)
- Sonoko Saito
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yuki Saito
- Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan; Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Showbu Sato
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Satomi Aoki
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Harumi Fujita
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yoshihiro Ito
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Noriko Ono
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Takeru Funakoshi
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tomoko Kawai
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan
| | - Hisato Suzuki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Takashi Sasaki
- Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tomoyo Tanaka
- R&D department, Japan Tissue Engineering Co., Ltd., Aichi 443-0022, Japan
| | - Masukazu Inoie
- R&D department, Japan Tissue Engineering Co., Ltd., Aichi 443-0022, Japan
| | - Kenichiro Hata
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan; Department of Human Molecular Genetics, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
| | - Keisuke Kataoka
- Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Kenjiro Kosaki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Kazuhiko Nakabayashi
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan.
| | - Akiharu Kubo
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan; Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan.
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15
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Jairaman A, Badiger VA, Raj S, Nair KV, Balan S, Narayanan DL. A novel homozygous variant in PMVK is associated with enhanced IL1β secretion and a hyper-IgD syndrome-like phenotype. Clin Genet 2024; 105:302-307. [PMID: 38018277 DOI: 10.1111/cge.14451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/26/2023] [Accepted: 10/30/2023] [Indexed: 11/30/2023]
Abstract
The evolutionarily conserved mevalonate pathway plays an important role in the synthesis of cholesterol and isoprenoid compounds. Mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK) enzymes regulate key rate-limiting steps in this pathway by sequentially phosphorylating mevalonic acid to yield downstream metabolites that regulate protein prenylation and cell signaling. Biallelic pathogenic variants in MVK cause a spectrum of rare autoinflammatory disorders that encompass milder forms of hyper-IgD syndrome (HIDS) at one end and the more severe mevalonic aciduria on the other. In contrast, pathogenic variants reported in PMVK are heterozygous and associated with porokeratosis, a skin disorder with no systemic manifestations. Recently, biallelic variants in PMVK were reported as a cause for an autoinflammatory disorder for the first time in two unrelated patients. In this study, we describe a child with recurrent arthritis and a HIDS-like phenotype harboring a novel homozygous variant c.398 C>T (p.Ala133Val) in PMVK. Mononuclear cells isolated from the patient showed significantly elevated production of interleukin 1β, a key cytokine that shapes the inflammatory response in HIDS. Protein modeling studies suggested potential defects in PMVK enzyme activity. These results posit a further expanding of the genotypic spectrum of autoinflammatory disease to include biallelic PMVK variants.
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Affiliation(s)
- Amit Jairaman
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
| | - Vaishnavi Ashok Badiger
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
| | - Spoorthy Raj
- Department of Rheumatology and Clinical Immunology, Amrita Institute of Medical Sciences, Kochi, India
| | - Karthik Vijay Nair
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
| | - Suma Balan
- Department of Rheumatology and Clinical Immunology, Amrita Institute of Medical Sciences, Kochi, India
| | - Dhanya Lakshmi Narayanan
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India
- DBT-Wellcome Trust India Alliance Early Career Clinical and Public Health Research Fellow, Hyderabad, India
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16
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Akiyama M. Diseases categorized as autoinflammatory keratinization diseases (AiKDs), and their pathologies and treatments. NAGOYA JOURNAL OF MEDICAL SCIENCE 2024; 86:1-15. [PMID: 38505726 PMCID: PMC10945231 DOI: 10.18999/nagjms.86.1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 07/06/2023] [Indexed: 03/21/2024]
Abstract
Whole-exome and whole-genome sequencing have become widespread in approximately the last 15 years, and the predisposing factors and pathomechanisms of inflammatory keratinization diseases, which have been unknown for a long time, have gradually been revealed. Hence, various inflammatory keratinization diseases are recognized to cause innate immunity hyperactivation. Therefore, we have been advocating for the clinical entity, "autoinflammatory keratinization diseases (AiKDs)" since 2017. AiKDs are inflammatory keratinization diseases caused by autoinflammatory-related pathomechanisms in the skin. The aberrant activation of innate immunity and the resultant autoinflammation in the epidermis and the superficial dermis in AiKDs cause hyperkeratosis in the epidermis. Our initially proposed concept of AiKDs included generalized pustular psoriasis and related conditions, pityriasis rubra pilaris type V, and familial keratosis lichenoides chronica. Since then, the number of diseases known to be AiKDs has increased as previously unknown disease-causing factors and pathogenetic mechanisms of inflammatory keratinization diseases have been clarified one by one. To date, porokeratosis, hidradenitis suppurative, keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome, and AiKDs associated with epidermal growth factor receptor (EGFR) deficiency or with hepatitis and autism have been recognized as AiKDs. The concept of AiKDs is considered extremely useful in our precise understanding of the pathogeneses behind inflammatory keratinization diseases and our appropriate treatment method selection. The number of AiKDs is expected to grow with the clarification of the pathomechanisms of further inflammatory keratinization diseases.
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Affiliation(s)
- Masashi Akiyama
- Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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17
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Wang X, Ouyang X, Zhang D, Zhu Y, Wu L, Xiao Z, Yu S, Li W, Li C. Two Novel and Three Recurrent Mutations in the Mevalonate Pathway Genes in Chinese Patients with Porokeratosis. Clin Cosmet Investig Dermatol 2024; 17:191-197. [PMID: 38283795 PMCID: PMC10822103 DOI: 10.2147/ccid.s444985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 01/18/2024] [Indexed: 01/30/2024]
Abstract
PURPOSE Porokeratosis (PK) is a chronic autosomal-dominant cutaneous keratinization disorder exhibiting clinical and genetic heterogeneity. Mevalonate decarboxylase (MVD), farnesyl diphosphate synthase (FDPS), phosphomevalonate kinase(PMVK), and mevalonate kinase genes(MVK), which encode the mevalonate pathway, are disease-causing genes in PK. PATIENTS AND METHODS Data and blood samples were collected from two Chinese families and five sporadic patients with porokeratosis. Whole-exome and Sanger sequencing were performed to detect pathogenic gene mutation in the patients. RESULTS Five heterozygous mutations were identified, including a novel FDPS stop-gain mutation c.438T>G (p.Tyr146Ter), a novel MVD missense mutation c.683G>C (p.R228P), and three previously reported MVD mutations: c.746T>C (p.F249S), c.875A>G (p.N292S), and c.1111_1113del (p.371_371del). The novel FDPS c.438T>G mutation was predicted as "disease-causing" (p = 1) by Mutation Taster. The other novel MVD c.683G>C was also predicted as "deleterious" (score = 0.00) by Sorting Intolerant From Tolerant (SIFT), "probably damaging" (score = 1) by PolyPhen2, and "disease-causing" (p = 0.999) by Mutation Taster. CONCLUSION Our results extended the mutation spectrum of mevalonate pathway genes in porokeratosis and provided useful strategies for a more accurate diagnosis and genetic counseling.
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Affiliation(s)
- Xiuping Wang
- Department of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Xiaoliang Ouyang
- Department of Plastic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Deng Zhang
- Department of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Yunxia Zhu
- Department of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Liang Wu
- Department of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Zhen Xiao
- Department of Dermatology, Taiyuan Central Hospital, Taiyuan, Shanxi, People’s Republic of China
| | - Simin Yu
- Department of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Wei Li
- Department of Plastic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
| | - Chunming Li
- Department of Dermatology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China
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18
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Jin Y, Chen F, Nabatanzi A, Wu T, Sun Y, Chen S, Huang C. Clinicopathological retrospective analysis of porokeratosis ptychotropica and genitogluteal porokeratosis: confusion-prone but essentially different twins. Arch Dermatol Res 2023; 315:2841-2843. [PMID: 37642699 DOI: 10.1007/s00403-023-02694-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/18/2023] [Accepted: 07/27/2023] [Indexed: 08/31/2023]
Affiliation(s)
- Yifan Jin
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue No.1277, Hankou, Wuhan, 430022, Hubei, China
| | - Fangqi Chen
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue No.1277, Hankou, Wuhan, 430022, Hubei, China
| | - Amelia Nabatanzi
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue No.1277, Hankou, Wuhan, 430022, Hubei, China
| | - Ting Wu
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue No.1277, Hankou, Wuhan, 430022, Hubei, China
| | - Yanhong Sun
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.
| | - Siyuan Chen
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue No.1277, Hankou, Wuhan, 430022, Hubei, China.
| | - Changzheng Huang
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue No.1277, Hankou, Wuhan, 430022, Hubei, China.
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19
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Pietkiewicz P, Korecka K, Salwowska N, Kohut I, Adhikari A, Bowszyc-Dmochowska M, Pogorzelska-Antkowiak A, Navarrete-Dechent C. Porokeratoses-A Comprehensive Review on the Genetics and Metabolomics, Imaging Methods and Management of Common Clinical Variants. Metabolites 2023; 13:1176. [PMID: 38132857 PMCID: PMC10744643 DOI: 10.3390/metabo13121176] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/17/2023] [Accepted: 11/24/2023] [Indexed: 12/23/2023] Open
Abstract
Porokeratosis is a heterogeneous group of keratinising disorders characterised by the presence of particular microscopic structural changes, namely the presence of the cornoid lamella. This structure develops as a consequence of a defective isoprenoid pathway, critical for cholesterol synthesis. Commonly recognised variants include disseminated superficial actinic porokeratosis, disseminated superficial porokeratosis, porokeratosis of Mibelli, palmoplantar porokeratosis (including porokeratosis palmaris et plantaris disseminata and punctate porokeratosis), linear porokeratosis, verrucous porokeratosis (also known as genitogluteal porokeratosis), follicular porokeratosis and porokeratoma. Apart from the clinical presentation and epidemiology of each variant listed, this review aims at providing up-to-date information on the precise genetic background, introduces imaging methods facilitating the diagnosis (conventional and ultraviolet-induced fluorescence dermatoscopy, reflectance confocal microscopy and pathology), discusses their oncogenic potential and reviews the literature data on the efficacy of the treatment used, including the drugs directly targeting the isoprenoid-mevalonate pathway.
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Affiliation(s)
- Paweł Pietkiewicz
- Dermatology Private Practice, 61-683 Poznan, Poland
- Polish Dermatoscopy Group, 61-683 Poznan, Poland; (K.K.); (N.S.)
| | - Katarzyna Korecka
- Polish Dermatoscopy Group, 61-683 Poznan, Poland; (K.K.); (N.S.)
- Department of Dermatology and Venereology, Poznan University of Medical Sciences, 60-356 Poznan, Poland
| | - Natalia Salwowska
- Polish Dermatoscopy Group, 61-683 Poznan, Poland; (K.K.); (N.S.)
- Department of Dermatology, School of Medicine, Medical University of Silesia, 40-027 Katowice, Poland
| | - Ihor Kohut
- Skin Health Center, 46027 Ternopil, Ukraine;
| | | | - Monika Bowszyc-Dmochowska
- Cutaneous Histopathology and Immunopathology Section, Department of Dermatology, Poznan University of Medical Sciences, 60-356 Poznan, Poland;
| | | | - Cristian Navarrete-Dechent
- Melanoma and Skin Cancer Unit, Department of Dermatology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile;
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20
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Maierhofer U, Dhirad A, Papathomas T. Eruptive Pruritic Maculopapular Rash Following Pfizer-BioNTech COVID-19 Vaccination: Answer. Am J Dermatopathol 2023; 45:662-664. [PMID: 37625807 DOI: 10.1097/dad.0000000000002506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2023]
Affiliation(s)
- Urša Maierhofer
- Department of Pathology, Vestre Viken Hospital Trust, Drammen, Norway
| | - Anita Dhirad
- KAL Klinikken Oslo, Oslo, Norway
- Hudlege Anita Dhirad AS, Drammen, Norway; and
| | - Thomas Papathomas
- Department of Pathology, Vestre Viken Hospital Trust, Drammen, Norway
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
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21
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Mei Q, Xing F, Yin Y, Yuan C. Case Report: A Novel MVK Missense Mutation in the Sporadic Porokeratosis Ptychotropica in China. Clin Cosmet Investig Dermatol 2023; 16:1325-1329. [PMID: 37250911 PMCID: PMC10224681 DOI: 10.2147/ccid.s408016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 05/10/2023] [Indexed: 05/31/2023]
Abstract
Porokeratosis ptychotropica (PPt) is a rare type of porokeratosis (PK) characterized by pruritic, reddish-brownish verrucous papules, and plaques usually around genital area or buttocks. Here, a case of a 70-year-old woman who was diagnosed as PPt was reported. The patient suffered from severe pruritic papules and plaques in the buttock region and pubis for 4 years. The skin lesions were giant, well-defined brown plaques with many satellite papules scattered around. Both clinical manifestations and histopathological features supported the diagnosis of PPt. In review of the identified mutation was found in patients with disseminated superficial actinic porokeratosis (DSAP) combined with PPt, while its unclear in PPt. To investigate the hypothesis that the variant reported in the present case report may played as an independent "likely pathogenic factor" of PPt. Consequently, a de novo missense pathogenic mutation in the MVK gene was identified in this case. Unexpectedly, it is a first report of a novel MVK mutation in sporadic PPt. This rare case suggested an isogenetic background between PPt and DSAP, which may help to explore the underlying pathogenesis of PPt.
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Affiliation(s)
- Qin Mei
- Department of Dermatology, Dermatology Hospital of Fuzhou, Fuzhou, Fujian, People’s Republic of China
| | - Fengling Xing
- Department of Dermatology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Yue Yin
- Department of Dermatology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
| | - Chengda Yuan
- Department of Dermatology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China
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22
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Inci R, Zagoras T, Kantere D, Holmström P, Gillstedt M, Polesie S, Peltonen S. Porokeratosis is one of the most common genodermatoses and is associated with an increased risk of keratinocyte cancer and melanoma. J Eur Acad Dermatol Venereol 2023; 37:420-427. [PMID: 36152004 PMCID: PMC10092613 DOI: 10.1111/jdv.18587] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/17/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND Porokeratosis is a clinically heterogeneous group of keratinization disorders with a genetic background mainly affecting the mevalonate pathway, which is involved in the synthesis of cholesterol, an essential component for the formation of the extracellular lipid lamellae in the stratum corneum. Porokeratosis is reportedly associated with an increased risk of keratinocyte cancer, but to date, no large epidemiological studies have been conducted to further address this association. OBJECTIVES The first objective was to characterize a cohort of patients diagnosed with porokeratosis at the Department of Dermatology and Venereology, Sahlgrenska University Hospital (SU), Gothenburg, Sweden. The second objective was to conduct a nationwide registry-based cohort study to investigate the association, if any, between porokeratosis and the cutaneous malignancies squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma. METHODS For the SU cohort, the hospital registry was searched for patients with a diagnosis of porokeratosis recorded between 2016 and 2020. Clinical data were extracted from the records of the identified patients. For the nationwide cohort, national registries were searched to identify patients with a diagnosis of porokeratosis between 2001 and 2020. A tenfold control cohort was formed by Statistics Sweden. The data was cross-referenced with the Swedish Cancer Register to study the associations between porokeratosis and SCC, BCC and melanoma. RESULTS Disseminated superficial actinic porokeratosis was the most common clinical type among the 108 patients in the SU cohort. In the nationwide search, 2277 patients with porokeratosis were identified (prevalence 1/4132). Porokeratosis was associated with an increased risk for SCC, BCC and melanoma with hazard ratios (95% CI) of 4.3 (3.4-5.4), 2.42 (1.97-2.98) and 1.83 (1.18-2.82), respectively, in the patient cohort, compared to the matched control group. CONCLUSION Porokeratosis is a common genodermatosis, and it is associated with an enhanced risk of skin cancer.
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Affiliation(s)
- Rahime Inci
- Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Dermatology and Venereology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Theofanis Zagoras
- Department of Clinical Genetics and Genomics, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Despoina Kantere
- Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Dermatology and Venereology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Peter Holmström
- Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Dermatology and Venereology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Martin Gillstedt
- Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Dermatology and Venereology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Sam Polesie
- Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Dermatology and Venereology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Sirkku Peltonen
- Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Dermatology and Venereology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
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Yang J, Du YQ, Fang XY, Li B, Xi ZQ, Feng WL. Linear porokeratosis of the foot with dermoscopic manifestations: A case report. World J Clin Cases 2022; 10:11585-11589. [PMID: 36387824 PMCID: PMC9649560 DOI: 10.12998/wjcc.v10.i31.11585] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/14/2022] [Accepted: 10/09/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Porokeratosis (PK) is a common autosomal dominant chronic progressive dyskeratosis with various clinical manifestations. Based on clinical manifestations, porokeratosis can be classified as porokeratosis of mibelli, disseminated superficial porokeratosis, disseminated superficial actinic porokeratosis, linear porokeratosis (LP), porokeratosis palmaris et plantaris disseminata, porokeratosis punctata, popular PK, hyperkeratosis PK, inflammatory PK, verrucous PK, and mixed types. We report a case of LP in a child and describe its dermoscopic findings.
CASE SUMMARY Linear porokeratosis is a rare PK. The patient presented with unilateral keratinizing maculopapular rash of the foot in childhood. The patient underwent skin pathology and dermoscopy, and was treated with liquid nitrogen freezing and topical drugs.
CONCLUSION From this case we take-away that LP is a rare disease, by the dermoscopic we can identify it.
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Affiliation(s)
- Jing Yang
- Department of Dermatology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Yi-Qing Du
- Department of Dermatology, Gaoping City People’s Hospital, Gaoping 048400, Shanxi Province, China
| | - Xiao-Ya Fang
- Department of Dermatology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Bo Li
- Department of Dermatology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Zhi-Qin Xi
- Department of Dermatology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Wen-Li Feng
- Department of Dermatology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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24
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MicroRNA-874 targets phosphomevalonate kinase and inhibits cancer cell growth via the mevalonate pathway. Sci Rep 2022; 12:18443. [PMID: 36323841 PMCID: PMC9630378 DOI: 10.1038/s41598-022-23205-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 10/26/2022] [Indexed: 11/06/2022] Open
Abstract
The microRNA (miR) miR-874, a potential tumour suppressor, causes cell death via target gene suppression in various cancer types. Mevalonate pathway inhibition also causes cell death in breast cancer. However, the relationship between the mevalonate pathway and miR-874-induced apoptosis or its association with the tumour suppressor p53 has not been elucidated. We identified phosphomevalonate kinase (PMVK), a key mevalonate pathway enzyme, and sterol regulatory element-binding factor 2 (SREBF2), the master cholesterol biosynthesis regulator, as direct miR‑874 targets. Next-generation sequencing analysis revealed a significant miR-874-mediated downregulation of PMVK and SREBF2 gene expression and p53 pathway enrichment. Luciferase reporter assays showed that miR-874 directly regulated PMVK and SREBF2. miR-874-induced apoptosis was p53 dependent, and single-cell RNA sequencing analysis demonstrated that miR-874 transfection resulted in apoptosis and p53 pathway activation. Downregulation of PMVK expression also caused cell cycle arrest and p53 pathway activation, which was rescued by geranylgeranyl pyrophosphate (GGPP) supplementation. Analysis of The Cancer Genome Atlas (TCGA) database indicated a negative correlation between miR-874 and PMVK expression and between miR-874 and SREBF2 expression. These findings suggest that miR-874 suppresses the mevalonate pathway by targeting SREBF2 and PMVK, resulting in GGPP depletion, which activates the p53 pathway and promotes cycle arrest or apoptosis.
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25
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Kazlouskaya M, Brown RB, Marks KC. Persistent plaque on the buttock of a 5-year-old girl. Pediatr Dermatol 2022; 39:971-972. [PMID: 36440994 DOI: 10.1111/pde.15099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 07/15/2022] [Indexed: 11/29/2022]
Affiliation(s)
| | - Richard B Brown
- School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Katherine C Marks
- Department of Dermatology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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26
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Abstract
Annular lichenoid diseases encompass a diverse range of pathologies that present as circular, raised, or flat lesions that may vary in size and number. Examples include annular lichenoid dermatitis of youth, annular lichen planus, erythema dyschromicum perstans, erythema multiforme, fixed drug eruption, lichen sclerosus, neonatal lupus, porokeratosis, subacute cutaneous lupus erythematosus, and lichenoid syphilis. Clinical morphology and histopathology can differentiate these entities.
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27
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Twists and turns of the genetic story of mevalonate kinase-associated diseases: A review. Genes Dis 2022; 9:1000-1007. [PMID: 35685471 PMCID: PMC9170606 DOI: 10.1016/j.gendis.2021.05.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 04/19/2021] [Accepted: 05/12/2021] [Indexed: 11/26/2022] Open
Abstract
Mevalonate kinase (MK)-associated diseases encompass a broad spectrum of rare auto-inflammatory conditions, all resulting from pathogenic variants in the mevalonate kinase gene (MVK). Their clinical manifestations are highly variable, ranging from more or less serious systemic disorders, such as hereditary recurrent fevers, to purely localized pathologies such as porokeratosis. The oldest condition identified as linked to this gene is a metabolic disease called mevalonic aciduria, and the most recent is disseminated superficial actinic porokeratosis, a disease limited to the skin. The modes of inheritance of MK-associated diseases also diverge among the different subtypes: recessive for the systemic subtypes and dominant with a post-zygotic somatic genetic alteration for MVK-associated porokeratosis. This review quickly retraces the historical steps that led to the description of the various MK-associated disease phenotypes and to a better understanding of their pathophysiology, then summarizes and compares the different genetic mechanisms involved in this group of disorders, and finally discusses the diverse causes that could underlie this phenotypic heterogeneity.
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28
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Kachroo AH, Vandeloo M, Greco BM, Abdullah M. Humanized yeast to model human biology, disease and evolution. Dis Model Mech 2022; 15:275614. [PMID: 35661208 PMCID: PMC9194483 DOI: 10.1242/dmm.049309] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
For decades, budding yeast, a single-cellular eukaryote, has provided remarkable insights into human biology. Yeast and humans share several thousand genes despite morphological and cellular differences and over a billion years of separate evolution. These genes encode critical cellular processes, the failure of which in humans results in disease. Although recent developments in genome engineering of mammalian cells permit genetic assays in human cell lines, there is still a need to develop biological reagents to study human disease variants in a high-throughput manner. Many protein-coding human genes can successfully substitute for their yeast equivalents and sustain yeast growth, thus opening up doors for developing direct assays of human gene function in a tractable system referred to as 'humanized yeast'. Humanized yeast permits the discovery of new human biology by measuring human protein activity in a simplified organismal context. This Review summarizes recent developments showing how humanized yeast can directly assay human gene function and explore variant effects at scale. Thus, by extending the 'awesome power of yeast genetics' to study human biology, humanizing yeast reinforces the high relevance of evolutionarily distant model organisms to explore human gene evolution, function and disease.
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Xu HJ, Wen GD. Mixed porokeratosis with a novel mevalonate kinase gene mutation: A case report. World J Clin Cases 2022; 10:4528-4534. [PMID: 35663074 PMCID: PMC9125269 DOI: 10.12998/wjcc.v10.i14.4528] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 12/11/2021] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Porokeratosis is a rare, acquired, or inherited disorder of keratinization. There are numerous clinical types of porokeratosis and they can coexist in one patient and multiple members of an affected family. However, coexistence of disseminated superficial actinic porokeratosis (DSAP) and porokeratosis ptychotropica (Ppt) is rare.
CASE SUMMARY A 45-year-old man presented with long-standing skin lesions. Physical examination identified numerous small, brown 2-mm to 4-mm patches on his face and several hyperkeratotic, verrucous plaques on his trunk and extremities. His father and one of his brothers also had similar lesions for years. Skin biopsies indicated a cornoid lamella in the epidermis. We identified c.155G>A mutation in the mevalonate kinase (MVK) gene, which converted a serine residue to asparagine (p.Ser52Asn) and was causative for porokeratosis in this family. A clinicopathologic diagnosis of DSAP and Ppt with a novel MVK gene mutation was made. The hyperkeratotic plaques on the patient’s scrotum were completely removed more than 10 times using a microwave knife.
CONCLUSION An unusual case of DSAP coexisting with Ppt harbored a novel MVK gene mutation also present in the patient’s family.
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Affiliation(s)
- Hong-Jun Xu
- Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Guang-Dong Wen
- Department of Dermatology, Peking University People's Hospital, Peking University, Beijing 100044, China
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30
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Tao L, Huang YK, Yan KX, Li CH, Shen L, Zhang ZH. A preliminary study of peripheral T-cell subsets in porokeratosis patients with MVK or MVD variants. SKIN HEALTH AND DISEASE 2022; 2:e82. [PMID: 35665211 PMCID: PMC9060116 DOI: 10.1002/ski2.82] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 12/15/2022]
Abstract
Background Porokeratosis (PK) is considered a skin‐specific autoinflammatory keratinization disease. Intriguingly, four causative genes of PK are in turn arranged in mevalonate pathway, with MVD variants being the commonest followed by MVK variants in a cohort of Chinese patients. Evidence indicates that mevalonate metabolites induce trained immunity in human monocytes and regulate T cells at multiple levels. Of note, γδT cells are dually regulated by intracellular and extracellular mevalonate metabolism. Aims To identify the possible differences in T‐cell between MVK or MVD variants from PK patients. Materials & Methods Targeted exome sequencing and exonic CNV screening were performed in 26 patients with PK. Sanger sequencing was used to validate all identified variants. Among them, 22 patients were identified with MVK or MVD variants. PBMCs from 22 PK patients and 27 normal controls (NCs) were analysed by flow cytometry for the frequencies of T cells subsets, including IFN‐γ‐, and TNF‐α‐producing T cells. Results There were 14 mutations identified in the 26 PK patients, including 6 novel mutations (MVK: c.118_226+1337dup, c.388_392delGATATinsC, c.613A>T, c.768G>C, and MVD: c.250C>T, c.988T>G). In contrast to NCs, significantly decreased frequencies of CD8+ and Vγ9Vδ2 T cells were observed in the PK patients with MVD variants. Moreover, it was found that dysregulated secretion of pro‐inflammatory cytokines by T cells in both PK patients with MVK and MVD variants. Conclusions Our findings enriched the Human Gene Mutation Databases and showed probable differences in peripheral T cells subsets between PK patients and controls.
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Affiliation(s)
- L Tao
- Department of Dermatology Huashan Hospital Shanghai Medical College of Fudan University Shanghai China
| | - Y K Huang
- Department of Dermatology Huashan Hospital Shanghai Medical College of Fudan University Shanghai China.,Department of Dermatology Xiamen Chang Gung Hospital Xiamen China
| | - K X Yan
- Department of Dermatology Huashan Hospital Shanghai Medical College of Fudan University Shanghai China
| | - C H Li
- Genesky Biotechnologies Inc Shanghai China
| | - L Shen
- Shanghai Institute of Immunology Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Z H Zhang
- Department of Dermatology Huashan Hospital Shanghai Medical College of Fudan University Shanghai China
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31
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Foster C, Tallon B. Porokeratosis: a differential diagnosis to consider in benign lichenoid keratosis. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2022; 15:56-62. [PMID: 35265253 PMCID: PMC8902476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/30/2021] [Indexed: 06/14/2023]
Abstract
Porokeratosis is a disorder of keratinization with many clinical variants. The histological hallmark feature of porokeratosis is a cornoid lamella. Other accompanying features include lichenoid inflammation, atrophy towards the centre of the lesion, dermal cytoid bodies, and adjacent lichenoid changes. Lichenoid keratosis is a benign cutaneous condition, thought to largely represent a degenerating seborrheic keratosis or solar lentigo. The classical histologic appearances are characterized by parakeratosis, epidermal acanthosis, and a dense band of lichenoid lymphocytic infiltrate. Since a lichenoid inflammatory reaction pattern can be seen in porokeratosis it has the potential to be misdiagnosed as a lichenoid keratosis if the cornoid lamella is not identified or missed due to sampling selection. We critically review 104 cases of benign lichenoid keratosis to establish whether any of these cases had features to support a diagnosis of porokeratosis. With 9.6% of cases considered for re-classification, we review clues to reaching this histologic diagnosis.
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Affiliation(s)
- Charlotte Foster
- Histopathology Department, Middlemore Hospital Auckland, New Zealand
| | - Ben Tallon
- Dermatology Division, Department of Anatomical Pathology, Pathlab 829 Cameron Road, Tauranga 3112, New Zealand
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32
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Akiyama M. Autoinflammatory keratinization diseases: The concept, diseases involved, and pathogeneses. DERMATOL SIN 2022. [DOI: 10.4103/1027-8117.365590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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33
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Savic S, Coe J, Laws P. Autoinflammation: Interferonopathies and Other Autoinflammatory Diseases. J Invest Dermatol 2021; 142:781-792. [PMID: 34887082 DOI: 10.1016/j.jid.2021.07.189] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 06/30/2021] [Accepted: 07/05/2021] [Indexed: 11/19/2022]
Abstract
The family of autoinflammatory diseases (AIDs) continues to expand and now includes over 40 genetically defined disorders. Their defining feature is a dysregulated inflammatory innate immune response. Many AIDs have overlapping clinical characteristics, and dermatological manifestations are common. Autoinflammatory features have also been recognized in more common dermatological conditions such as psoriasis. Furthermore, there is an increasing understanding that immunodeficiencies, autoimmune disorders, and even some allergic disorders share overlapping autoinflammatory features. The discovery that certain somatic mutations, arising within the bone marrow and restricted to the myeloid cell lineage can cause acquired AID heralds a new era of discoveries in this field.
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Affiliation(s)
- Sinisa Savic
- National Institute for Health Research (NIHR) Leeds Biomedical Research Centre, School of Medicine, University of Leeds, Leeds, United Kingdom; Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), School of Medicine, University of Leeds, Leeds, United Kingdom; Department of Allergy and Clinical Immunology, The Leeds Teaching Hospitals, National Health Service (NHS) Trust, Leeds, United Kingdom.
| | - James Coe
- Leeds Centre for Dermatology, Leeds Teaching Hospitals, National Health Service (NHS) Trust, Leeds, United Kingdom
| | - Philip Laws
- Leeds Centre for Dermatology, Leeds Teaching Hospitals, National Health Service (NHS) Trust, Leeds, United Kingdom
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Novel missense mutations of MVK and FDPS gene in Chinese patients with disseminated superficial actinic porokeratosis. Clin Chim Acta 2021; 523:441-445. [PMID: 34751146 DOI: 10.1016/j.cca.2021.10.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 10/25/2021] [Accepted: 10/25/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND AND AIMS Porokeratosis (PK) is a heterogeneous group of cutaneous keratinization disorders and has five clinical subtypes. DSAP is the most common clinical subtype and is characterized by multiple small, annular, anhidrotic, keratotic lesions predominantly on sun-exposed areas of the skin. It is an autosomal dominantly inherited epidermal keratinization disorder. However, studies on its molecular basis is limited. MATERIALS AND METHODS We performed mutation analysis of genes in four pedigrees and three sporadic cases of DSAP in the Chinese population. Genomic DNA was extracted from blood samples obtained from patients, unaffected family members, and 100 unrelated individuals. All exons and flanking intron sequences of the mevalonate kinase (MVK) and farnesyl diphosphate synthase (FDPS) genes were amplified. RESULTS One missense mutation in exon 7 (C.G677A) of the MVK gene was identified in pedigree 3, and one missense mutation in exon 5 (C.C535T) of the FDPS gene was identified in sporadic case 3. No mutation was detected in the MVK and FDPS genes in the remaining three pedigrees and two sporadic cases with DSAP. CONCLUSION Our results may be useful for genetic counseling and prenatal diagnosis of affected families and for expanding the repertoire of MVK and FDPS mutations underlying DSAP.
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35
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Politiek FA, Waterham HR. Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency. Front Immunol 2021; 12:724991. [PMID: 34539662 PMCID: PMC8446354 DOI: 10.3389/fimmu.2021.724991] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/12/2021] [Indexed: 12/25/2022] Open
Abstract
Mevalonate kinase deficiency (MKD) is an autoinflammatory metabolic disorder characterized by life-long recurring episodes of fever and inflammation, often without clear cause. MKD is caused by bi-allelic pathogenic variants in the MVK gene, resulting in a decreased activity of the encoded enzyme mevalonate kinase (MK). MK is an essential enzyme in the isoprenoid biosynthesis pathway, which generates both non-sterol and sterol isoprenoids. The inflammatory symptoms of patients with MKD point to a major role for isoprenoids in the regulation of the innate immune system. In particular a temporary shortage of the non-sterol isoprenoid geranylgeranyl pyrophosphate (GGPP) is increasingly linked with inflammation in MKD. The shortage of GGPP compromises protein prenylation, which is thought to be one of the main causes leading to the inflammatory episodes in MKD. In this review, we discuss current views and the state of knowledge of the pathogenetic mechanisms in MKD, with particular focus on the role of compromised protein prenylation.
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Affiliation(s)
- Frouwkje A Politiek
- Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Hans R Waterham
- Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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36
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A proteome-wide atlas of lysine-reactive chemistry. Nat Chem 2021; 13:1081-1092. [PMID: 34504315 DOI: 10.1038/s41557-021-00765-4] [Citation(s) in RCA: 137] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 07/05/2021] [Indexed: 01/24/2023]
Abstract
Recent advances in chemical proteomics have begun to characterize the reactivity and ligandability of lysines on a global scale. Yet, only a limited diversity of aminophilic electrophiles have been evaluated for interactions with the lysine proteome. Here, we report an in-depth profiling of >30 uncharted aminophilic chemotypes that greatly expands the content of ligandable lysines in human proteins. Aminophilic electrophiles showed disparate proteomic reactivities that range from selective interactions with a handful of lysines to, for a set of dicarboxaldehyde fragments, remarkably broad engagement of the covalent small-molecule-lysine interactions captured by the entire library. We used these latter 'scout' electrophiles to efficiently map ligandable lysines in primary human immune cells under stimulatory conditions. Finally, we show that aminophilic compounds perturb diverse biochemical functions through site-selective modification of lysines in proteins, including protein-RNA interactions implicated in innate immune responses. These findings support the broad potential of covalent chemistry for targeting functional lysines in the human proteome.
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37
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Huber F, Lautenschlager S. [CME Dermatology 24: Porokeratosis]. PRAXIS 2021; 110:709-716. [PMID: 34583541 DOI: 10.1024/1661-8157/a003756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
CME Dermatology 24: Porokeratosis Abstract. Porokeratoses are a heterogeneous group of cornification disorders with the characteristic histological feature of the cornoid lamellae in the area of the marginal ridge. It is a rare but characteristic disease that occurs primarily in adulthood. Men are slightly more likely to be affected. The etiopathogenesis that leads to the transformation of the keratinocytes remains unclear; associations with genetic mutations and trigger factors such as UV rays and immunosuppression were observed. Due to the risk of malignant degeneration, consistent sun protection and regular clinical controls should take place. Cryotherapy, ablative laser therapy, curettage, photodynamic therapy or topical application of fluorouracil (5-FU), imiquimod and retinoids can be used to treat itchy, painful or cosmetically disturbing porokeratoses, depending on the location and severity.
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Affiliation(s)
- Fabienne Huber
- Institut für Dermatologie und Venerologie, Stadtspital Zürich
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38
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Zhao Q, Yu B, Zhou H, Feng C, Zhang X, Zheng Y, Geng S. Generalized type 2 segmental disseminated superficial actinic porokeratosis coexisted with multiple cutaneous squamous cell carcinomas: Analysis of two cases. INDIAN J PATHOL MICR 2021; 63:634-636. [PMID: 33154323 DOI: 10.4103/ijpm.ijpm_987_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Porokeratosis (PK) is defined as hyperpigmented macules or patches with a distinctive, ridge-like hyperkeratotic border which is histologically characterized by a cornoid lamella. Here, we report two cases of linear porokeratosis which converted to multiple cutaneous squamous cell carcinoma after long history progression. In addition, patient 2 was accompanied by secondary dermal amyloid deposits, which was rare reported.
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Affiliation(s)
- Qiang Zhao
- Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Biao Yu
- Department of Dermatology, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Hongmei Zhou
- Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Cheng Feng
- Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Xinyue Zhang
- Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Yi Zheng
- Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Songmei Geng
- Department of Dermatology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
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Abstract
BACKGROUND The MVD gene mutations are identified in porokeratosis, which is considered a skin-specific autoinflammatory keratinization disease. However, the biological function of MVD gene remains largely unknown. Therefore, we analyzed the function of mvda gene, orthologous to the human MVD gene, in developing zebrafish. METHODS Morpholino antisense oligonucleotide technique was used to generate mvda loss-of-function phenotypes. Knockdown of mvda was confirmed by RT-PCR and Sanger sequencing. Scanning and transmission electron microscopy were performed to analyze the morphology of the epidermis. Angiogenesis study was presented using the Tg(fli1a:EGFP)y1 transgenic strain. In addition, acridine orange staining was used to examine the apoptotic cells in vivo. RESULTS As expected, the mvda morphants showed abnormal morphology of the epidermis. Moreover, we observed ectopic sprouts in trunk angiogenesis and impaired formation of the caudal vein plexus in the mvda-deficient zebrafish. Besides, increased apoptosis was found throughout the tail, heart, and eyes in mvda zebrafish morphants. CONCLUSIONS These findings indicated the essential role of mvda in the early development of zebrafish. This was the first in vivo knockdown study of the zebrafish mvda gene, which might offer insight into the biological function of the human MVD gene.
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40
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Shiiya C, Aoki S, Nakabayashi K, Hata K, Amagai M, Kubo A. Linear and disseminated porokeratosis in one family showing identical and independent second hits in MVD among skin lesions, respectively: a proof-of-concept study. Br J Dermatol 2021; 184:1209-1212. [PMID: 33481264 DOI: 10.1111/bjd.19824] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/17/2021] [Accepted: 01/18/2021] [Indexed: 12/24/2022]
Affiliation(s)
- C Shiiya
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - S Aoki
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - K Nakabayashi
- Department of Maternal-Fetal Biology, National Centre for Child Health and Development, Tokyo, Japan
| | - K Hata
- Department of Maternal-Fetal Biology, National Centre for Child Health and Development, Tokyo, Japan
| | - M Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - A Kubo
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
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Boursier G, Rittore C, Milhavet F, Cuisset L, Touitou I. Mevalonate Kinase-Associated Diseases: Hunting for Phenotype-Genotype Correlation. J Clin Med 2021; 10:jcm10081552. [PMID: 33917151 PMCID: PMC8067830 DOI: 10.3390/jcm10081552] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/30/2021] [Accepted: 04/01/2021] [Indexed: 12/11/2022] Open
Abstract
Mevalonate kinase-associated diseases (MKAD) are caused by pathogenic mutations in the mevalonate kinase gene (MVK) and encompass several phenotypically different rare and hereditary autoinflammatory conditions. The most serious is a recessive systemic metabolic disease called mevalonic aciduria, and the most recently recognized is disseminated superficial actinic porokeratosis, a dominant disease limited to the skin. To evaluate a possible correlation between genotypes and (1) the different MKAD clinical subtypes or (2) the occurrence of severe manifestations, data were reviewed for all patients with MVK variants described in the literature (N = 346), as well as those referred to our center (N = 51). The genotypes including p.(Val377Ile) (homozygous or compound heterozygous) were more frequent in mild systemic forms but were also sometimes encountered with severe disease. We confirmed that amyloidosis was more prevalent in patients compound heterozygous for p.(Ile268Thr) and p.(Val377Ile) than in others and revealed new associations. Patients homozygous for p.(Leu264Phe), p.(Ala334Thr) or compound heterozygous for p.(His20Pro) and p.(Ala334Thr) had increased risk of severe neurological or ocular symptoms. All patients homozygous for p.(Leu264Phe) had a cataract. The variants associated with porokeratosis were relatively specific and more frequently caused a frameshift than in patients with other clinical forms (26% vs. 6%). We provide practical recommendations focusing on phenotype-genotype correlation in MKAD that could be helpful for prophylactic management.
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Affiliation(s)
- Guilaine Boursier
- Department of Medical Genetics, Rare Diseases and Personalized Medicine, Rare and Autoinflammatory Diseases Unit, CHU, 34295 Montpellier, France; (G.B.); (C.R.); (F.M.)
| | - Cécile Rittore
- Department of Medical Genetics, Rare Diseases and Personalized Medicine, Rare and Autoinflammatory Diseases Unit, CHU, 34295 Montpellier, France; (G.B.); (C.R.); (F.M.)
| | - Florian Milhavet
- Department of Medical Genetics, Rare Diseases and Personalized Medicine, Rare and Autoinflammatory Diseases Unit, CHU, 34295 Montpellier, France; (G.B.); (C.R.); (F.M.)
- IRMB, University of Montpellier, INSERM, 34295 Montpellier, France
| | - Laurence Cuisset
- Genetic and Molecular Biology Laboratory, Cochin Hospital, 75014 Paris, France;
| | - Isabelle Touitou
- Department of Medical Genetics, Rare Diseases and Personalized Medicine, Rare and Autoinflammatory Diseases Unit, CHU, 34295 Montpellier, France; (G.B.); (C.R.); (F.M.)
- IRMB, University of Montpellier, INSERM, 34295 Montpellier, France
- Correspondence:
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42
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Lee S, Nam M, Lee AR, Lee J, Woo J, Kang NS, Balupuri A, Lee M, Kim SY, Ro H, Choi YW, Kim DU, Hoe KL. Systematic Target Screening Revealed That Tif302 Could Be an Off-Target of the Antifungal Terbinafine in Fission Yeast. Biomol Ther (Seoul) 2021; 29:234-247. [PMID: 33223513 PMCID: PMC7921855 DOI: 10.4062/biomolther.2020.166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 11/22/2022] Open
Abstract
We used a heterozygous gene deletion library of fission yeasts comprising all essential and non-essential genes for a microarray screening of target genes of the antifungal terbinafine, which inhibits ergosterol synthesis via the Erg1 enzyme. We identified 14 heterozygous strains corresponding to 10 non-essential [7 ribosomal-protein (RP) coding genes, spt7, spt20, and elp2] and 4 essential genes (tif302, rpl2501, rpl31, and erg1). Expectedly, their erg1 mRNA and protein levels had decreased compared to the control strain SP286. When we studied the action mechanism of the non-essential target genes using cognate haploid deletion strains, knockout of SAGA-subunit genes caused a down-regulation in erg1 transcription compared to the control strain ED668. However, knockout of RP genes conferred no susceptibility to ergosterol-targeting antifungals. Surprisingly, the RP genes participated in the erg1 transcription as components of repressor complexes as observed in a comparison analysis of the experimental ratio of erg1 mRNA. To understand the action mechanism of the interaction between the drug and the novel essential target genes, we performed isobologram assays with terbinafine and econazole (or cycloheximide). Terbinafine susceptibility of the tif302 heterozygous strain was attributed to both decreased erg1 mRNA levels and inhibition of translation. Moreover, Tif302 was required for efficacy of both terbinafine and cycloheximide. Based on a molecular modeling analysis, terbinafine could directly bind to Tif302 in yeasts, suggesting Tif302 as a potential off-target of terbinafine. In conclusion, this genome-wide screening system can be harnessed for the identification and characterization of target genes under any condition of interest.
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Affiliation(s)
- Sol Lee
- Department of New Drug Development, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Miyoung Nam
- Department of New Drug Development, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Ah-Reum Lee
- Department of New Drug Development, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Jaewoong Lee
- Department of New Drug Development, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Jihye Woo
- Department of New Drug Development, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Nam Sook Kang
- Department of New Drug Development, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Anand Balupuri
- Department of New Drug Development, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Minho Lee
- Department of Life Science, Dongguk University-Seoul, Goyang 10326, Republic of Korea
| | - Seon-Young Kim
- Personalized Genomic Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
| | - Hyunju Ro
- Department of Biological Science, College of Bioscience & Biotechnology, Chungnam National University, Daejeon 34134, Republic of Korea
| | | | - Dong-Uk Kim
- Rare Disease Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 34141, Republic of Korea
| | - Kwang-Lae Hoe
- Department of New Drug Development, Chungnam National University, Daejeon 34134, Republic of Korea
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43
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Huang Y, Li Y, Wang X, Yu J, Cai Y, Zheng Z, Li R, Zhang S, Chen N, Asadollahpour Nanaei H, Hanif Q, Chen Q, Fu W, Li C, Cao X, Zhou G, Liu S, He S, Li W, Chen Y, Chen H, Lei C, Liu M, Jiang Y. An atlas of CNV maps in cattle, goat and sheep. SCIENCE CHINA-LIFE SCIENCES 2021; 64:1747-1764. [PMID: 33486588 DOI: 10.1007/s11427-020-1850-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 11/16/2020] [Indexed: 11/26/2022]
Abstract
Copy number variation (CNV) is the most prevalent type of genetic structural variation that has been recognized as an important source of phenotypic variation in humans, animals and plants. However, the mechanisms underlying the evolution of CNVs and their function in natural or artificial selection remain unknown. Here, we generated CNV region (CNVR) datasets which were diverged or shared among cattle, goat, and sheep, including 886 individuals from 171 diverse populations. Using 9 environmental factors for genome-wide association study (GWAS), we identified a series of candidate CNVRs, including genes relating to immunity, tick resistance, multi-drug resistance, and muscle development. The number of CNVRs shared between species is significantly higher than expected (P<0.00001), and these CNVRs may be more persist than the single nucleotide polymorphisms (SNPs) shared between species. We also identified genomic regions under long-term balancing selection and uncovered the potential diversity of the selected CNVRs close to the important functional genes. This study provides the evidence that balancing selection might be more common in mammals than previously considered, and might play an important role in the daily activities of these ruminant species.
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Affiliation(s)
- Yongzhen Huang
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Yunjia Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Xihong Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Jiantao Yu
- College of Information Engineering, Northwest A&F University, Yangling, 712100, China
| | - Yudong Cai
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Zhuqing Zheng
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Ran Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Shunjin Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Ningbo Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | | | - Quratulain Hanif
- National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Punjab, 577, Pakistan
- Pakistan Institute of Engineering & Applied Sciences (PIEAS), Nilore, 45650, Islamabad, Pakistan
| | - Qiuming Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Weiwei Fu
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Chao Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Xiukai Cao
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Guangxian Zhou
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Shudong Liu
- College of Information Engineering, Northwest A&F University, Yangling, 712100, China
| | - Sangang He
- Key Laboratory of Genetics Breeding and Reproduction of Grass feeding Livestock, Ministry of Agriculture, Biotechnology Research Institute, Xinjiang Academy of Animal Sciences, Urumqi, 830026, China
| | - Wenrong Li
- Key Laboratory of Genetics Breeding and Reproduction of Grass feeding Livestock, Ministry of Agriculture, Biotechnology Research Institute, Xinjiang Academy of Animal Sciences, Urumqi, 830026, China
| | - Yulin Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Hong Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Chuzhao Lei
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China
| | - Mingjun Liu
- Key Laboratory of Genetics Breeding and Reproduction of Grass feeding Livestock, Ministry of Agriculture, Biotechnology Research Institute, Xinjiang Academy of Animal Sciences, Urumqi, 830026, China
| | - Yu Jiang
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, China.
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44
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Peng JM, Xiao XM, Chen JW, Chen LF, Cheng B, Ji MK, Zhang ZH. Novel mutation in MVK gene for co-occurrence of disseminated superficial actinic porokeratosis with porokeratosis ptychotropica. J Dermatol 2021; 48:e137-e139. [PMID: 33458876 DOI: 10.1111/1346-8138.15748] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 11/25/2020] [Accepted: 12/11/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Jia-Mei Peng
- Department of Dermatology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Xue-Min Xiao
- Department of Dermatology, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Jia-Wen Chen
- Department of Dermatology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Li-Fen Chen
- Department of Dermatology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Bo Cheng
- Department of Dermatology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Ming-Kai Ji
- Department of Dermatology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Department of Dermatology, The Second Affiliated Hospital of Xiamen Medical Collage, Xiamen, China
| | - Zheng-Hua Zhang
- Department of Dermatology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
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45
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Qian W, Wu J, Tang H, Zhen Q, Ge H, Gao J, Chen J, Chang Y, Wang W, Sun L. Mutation Analysis of the MVD Gene in a Chinese Family with Disseminated Superficial Actinic Porokeratosis and a Chinese Literature Review. Indian J Dermatol 2021; 66:126-131. [PMID: 34188266 PMCID: PMC8208265 DOI: 10.4103/ijd.ijd_226_18] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background: Porokeratosis (PK) is a rare, heterogeneous group of keratinization disorders with an autosomal dominant inheritance pattern and is characterized by the presence of cornoid lamella. Disseminated superficial actinic PK is the most encountered subtype and typically manifests as multiple, small annular plaques with atrophic centers and slightly raised hyperkeratotic edges. Seven associated mutations (SSH1, SART3, MVKP, MVK, MVD, FDPS, and SLC17A9) have been reported in disseminated superficial actinic PK patients. Aim: We searched a Chinese disseminated superficial porokeratosis (DSAP) family to detect the causative genes. In the meantime, we reviewed the articles reported about DSAP in Chinese population, summarizing their clinical manifestations and discussing the incidence of DSAP in Chinese population. Materials and Methods: Sanger sequencing on the MVD and MVK genes was performed to identify the pathogenic mutation in a Chinese family with DSAP. Literature for DSAP cases reported in Chinese populations was searched by Sinomed and PubMed. Results: We identified the c. 875A > G (p. Asn292Ser) mutation in the MVD gene in the family. Conclusions: That mutation was a hotspot mutation. Literature review showed that the age of onset in DSAP family was earlier than that in sporadic patients; the lesion is common in the face in Chinese population which is distinct from studies in Caucasians; ultraviolet exposure is the main aggravating factor.
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Affiliation(s)
- Wenjun Qian
- Department of Dermatology at First Hospital, Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Department of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, China
| | - Jing Wu
- Department of Dermatology at First Hospital, Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Department of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, China
| | - Huayang Tang
- Department of Dermatology at First Hospital, Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Department of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, China
| | - Qi Zhen
- Department of Dermatology at First Hospital, Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Department of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, China
| | - Huiyao Ge
- Department of Dermatology at First Hospital, Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Department of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, China
| | - Jinping Gao
- Department of Dermatology at First Hospital, Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Department of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, China
| | - Jingjing Chen
- Department of Dermatology at First Hospital, Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Department of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, China
| | - Yuling Chang
- Department of Dermatology at First Hospital, Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Department of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, China
| | - Wenjun Wang
- Department of Dermatology at First Hospital, Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Department of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, China
| | - Liangdan Sun
- Department of Dermatology at First Hospital, Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Department of Dermatology, Key Laboratory of Dermatology, Anhui Medical University, Ministry of Education, Hefei, China.,Department of Dermatology, Anhui Province Key Laboratory of Major Autoimmune Disease, Hefei, China
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46
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Saleva-Stateva M, Hess M, Technau-Hafsi K, Weibel L, Badea MA, Boente MDC, Theiler M, Fiandrino MJ, Hoeger P, Zimmer A, Rafei-Shamsabadi D, Balabanova M, Fischer J, Boerries M, Has C. Molecular characterization and natural history of linear porokeratosis: A case series. J Am Acad Dermatol 2020; 85:1603-1606. [PMID: 33279647 DOI: 10.1016/j.jaad.2020.11.061] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 11/26/2022]
Affiliation(s)
- Mina Saleva-Stateva
- Department of Dermatology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; Department of Dermatology and Venereology, Alexandrovska University Hospital, Sofia, Bulgaria
| | - Maria Hess
- Institute of Medical Bioinformatics and System Medicine, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Kristin Technau-Hafsi
- Department of Dermatology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Lisa Weibel
- Pediatric Skin Center, Dermatology Department, University Children's Hospital Zurich, Zürich, Switzerland
| | - Mihai-Alexandru Badea
- Dermatology Department, University of Medicine, Pharmacy, Science and Technology of Targu-Mures, Targu-Mures, Romania
| | | | - Martin Theiler
- Pediatric Skin Center, Dermatology Department, University Children's Hospital Zurich, Zürich, Switzerland
| | | | - Peter Hoeger
- Catholic Children's Hospital, Wilhelmstift, Hamburg, Germany
| | - Andreas Zimmer
- Institute of Human Genetics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - David Rafei-Shamsabadi
- Department of Dermatology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Maria Balabanova
- Department of Dermatology and Venereology, Alexandrovska University Hospital, Sofia, Bulgaria
| | - Judith Fischer
- Institute of Human Genetics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Melanie Boerries
- Institute of Medical Bioinformatics and System Medicine, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; Comprehensive Cancer Center Freiburg (CCCF), Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Cristina Has
- Department of Dermatology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
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47
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Twenty-two novel mutations in a Chinese cohort of 137 patients with porokeratosis were identified using microfluidics (Fluidigm). J Dermatol Sci 2020; 101:75-77. [PMID: 33168400 DOI: 10.1016/j.jdermsci.2020.10.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 10/09/2020] [Accepted: 10/21/2020] [Indexed: 11/24/2022]
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48
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Li M, Jin R, Qi Y, Zhou H, Zhu T, Liu L, Gu Y, Luan K, Luo X, Zhang S. Cholesterol partially rescues the inhibition effect of pravastatin on keratinocytes proliferation by regulating cell cycle relative proteins through AKT and ERK pathway. Dermatol Ther 2020; 33:e14305. [PMID: 32926496 DOI: 10.1111/dth.14305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/18/2020] [Accepted: 09/10/2020] [Indexed: 11/28/2022]
Abstract
Mevalonate pathway plays a key role in skin physiological process in human. Recently, it has been reported that mutation of some genes in the mevalonate pathway cause disseminated superficial actinic porokeratosis (DSAP). But the pathogenesis is still unknown. Pravastatin (PRA), one of HMG-CoA reductase (HMGCR) inhibitors, has been found to inhibit cells proliferation, including keratinocytes (KCs). In this study, we use PRA to block the mevalonate pathway in KCs with or without the down-stream intermediate products replenishment. The results demonstrated that PRA strongly inhibited proliferation of KCs and caused the G0 /G1 arrest. When some down-stream intermediate products were added, only cholesterol (CH) could partially rescue the inhibition effect of PRA on KCs proliferation, but not other products, such as mevalonic acid, farnesyl pyrophosphate or geranylgeranyl pyrophosphate. Mechanistic analysis revealed that PRA down-regulated expression of cyclin B1, but up-regulated cyclin E and p21 expression. And PRA increased the phosphorylation level of Protein Kinase B (AKT) but decreased the phosphorylation level of Extracellular Signal Regulated Kinase (ERK1/2). CH could attenuate the elevated cyclin E and activated AKT induced by PRA. These results indicated that CH could rescue the proliferation inhibition of KCs caused by PRA, which laid a foundation for elucidating the pathogenesis of DSAP clearly.
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Affiliation(s)
- Mingcong Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Rui Jin
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Yinliang Qi
- General Department of Hyperbaric Oxygen, Affiliated Hefei Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hong Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Tingting Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Li Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Yanan Gu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Kang Luan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Xin Luo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Shengquan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
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49
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Saleva-Stateva M, Technau-Hafsi K, Frommherz L, Grüninger G, Jägle S, Dourmishev L, Miteva L, Fischer J, Has C. Recurrent MVD mutation in European patients with disseminated porokeratosis. Br J Dermatol 2020; 184:347-348. [PMID: 32767669 DOI: 10.1111/bjd.19467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/04/2020] [Accepted: 08/04/2020] [Indexed: 11/30/2022]
Affiliation(s)
- M Saleva-Stateva
- Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany.,Department of Dermatology and Venereology, Alexandrovska University Hospital, Sofia, Bulgaria
| | - K Technau-Hafsi
- Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - L Frommherz
- Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - G Grüninger
- Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - S Jägle
- Department of Human Genetics, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - L Dourmishev
- Department of Dermatology and Venereology, Alexandrovska University Hospital, Sofia, Bulgaria
| | - L Miteva
- Department of Dermatology and Venereology, Alexandrovska University Hospital, Sofia, Bulgaria
| | - J Fischer
- Department of Human Genetics, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - C Has
- Department of Dermatology, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany
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50
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Atzmony L, Choate KA. Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis. J Invest Dermatol 2020; 139:2409-2411. [PMID: 31753123 DOI: 10.1016/j.jid.2019.07.723] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 07/07/2019] [Accepted: 07/11/2019] [Indexed: 10/25/2022]
Abstract
Familial and sporadic porokeratosis are associated with germline heterozygous mutations in mevalonate pathway genes. Kubo et al. show that each skin lesion of disseminated superficial actinic porokeratosis originates from a postnatal keratinocyte clone with a different second-hit genetic event in the wild-type allele of the corresponding gene. They also confirm that linear porokeratosis derives from a single prenatal clone of keratinocytes with a second-hit genetic event.
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Affiliation(s)
- Lihi Atzmony
- Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Keith A Choate
- Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
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