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McFee RB. Lactose intolerance - A practical approach, Part 1. Dis Mon 2024; 70:101823. [PMID: 39627100 DOI: 10.1016/j.disamonth.2024.101823] [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] [Indexed: 12/16/2024]
Abstract
The toxicology, immunology and gastroenterology aspects of food remain important in clinical practice, as anyone treating food related anaphylaxis, or chronic intolerance syndromes can attest. Although entire editions of journals could focus on any one aspect of adverse effects from food, the following review addresses the important and prevalent gastrointestinal condition lactose intolerance and gastrointestinal (GI) conditions that have similar presentation but require different treatment.
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Affiliation(s)
- R B McFee
- Medical Director, Ellis Medical Toxicology, USA.
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2
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Babcock SJ, Flores-Marin D, Thiagarajah JR. The genetics of monogenic intestinal epithelial disorders. Hum Genet 2023; 142:613-654. [PMID: 36422736 PMCID: PMC10182130 DOI: 10.1007/s00439-022-02501-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/23/2022] [Indexed: 11/27/2022]
Abstract
Monogenic intestinal epithelial disorders, also known as congenital diarrheas and enteropathies (CoDEs), are a group of rare diseases that result from mutations in genes that primarily affect intestinal epithelial cell function. Patients with CoDE disorders generally present with infantile-onset diarrhea and poor growth, and often require intensive fluid and nutritional management. CoDE disorders can be classified into several categories that relate to broad areas of epithelial function, structure, and development. The advent of accessible and low-cost genetic sequencing has accelerated discovery in the field with over 45 different genes now associated with CoDE disorders. Despite this increasing knowledge in the causal genetics of disease, the underlying cellular pathophysiology remains incompletely understood for many disorders. Consequently, clinical management options for CoDE disorders are currently limited and there is an urgent need for new and disorder-specific therapies. In this review, we provide a general overview of CoDE disorders, including a historical perspective of the field and relationship to other monogenic disorders of the intestine. We describe the genetics, clinical presentation, and known pathophysiology for specific disorders. Lastly, we describe the major challenges relating to CoDE disorders, briefly outline key areas that need further study, and provide a perspective on the future genetic and therapeutic landscape.
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Affiliation(s)
- Stephen J Babcock
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Enders Rm 605, 300 Longwood Ave, Boston, MA, 02115, USA
| | - David Flores-Marin
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Enders Rm 605, 300 Longwood Ave, Boston, MA, 02115, USA
| | - Jay R Thiagarajah
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Harvard Medical School, Enders Rm 605, 300 Longwood Ave, Boston, MA, 02115, USA.
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Jajosky RP, Wu SC, Zheng L, Jajosky AN, Jajosky PG, Josephson CD, Hollenhorst MA, Sackstein R, Cummings RD, Arthur CM, Stowell SR. ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies. iScience 2023; 26:105798. [PMID: 36691627 PMCID: PMC9860303 DOI: 10.1016/j.isci.2022.105798] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Enzymes catalyze biochemical reactions and play critical roles in human health and disease. Enzyme variants and deficiencies can lead to variable expression of glycans, which can affect physiology, influence predilection for disease, and/or directly contribute to disease pathogenesis. Although certain well-characterized enzyme deficiencies result in overt disease, some of the most common enzyme deficiencies in humans form the basis of blood groups. These carbohydrate blood groups impact fundamental areas of clinical medicine, including the risk of infection and severity of infectious disease, bleeding risk, transfusion medicine, and tissue/organ transplantation. In this review, we examine the enzymes responsible for carbohydrate-based blood group antigen biosynthesis and their expression within the human population. We also consider the evolutionary selective pressures, e.g. malaria, that may account for the variation in carbohydrate structures and the implications of this biology for human disease.
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Affiliation(s)
- Ryan Philip Jajosky
- Joint Program in Transfusion Medicine, Brigham and Women’s Hospital, Harvard Medical School, 630E New Research Building, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
- Biconcavity Inc, Lilburn, GA, USA
| | - Shang-Chuen Wu
- Joint Program in Transfusion Medicine, Brigham and Women’s Hospital, Harvard Medical School, 630E New Research Building, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Leon Zheng
- Joint Program in Transfusion Medicine, Brigham and Women’s Hospital, Harvard Medical School, 630E New Research Building, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Audrey N. Jajosky
- University of Rochester Medical Center, Department of Pathology and Laboratory Medicine, West Henrietta, NY, USA
| | | | - Cassandra D. Josephson
- Cancer and Blood Disorders Institute and Blood Bank/Transfusion Medicine Division, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA
- Departments of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Marie A. Hollenhorst
- Department of Pathology and Department of Medicine, Stanford University, Stanford, CA, USA
| | - Robert Sackstein
- Translational Glycobiology Institute, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Richard D. Cummings
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Connie M. Arthur
- Joint Program in Transfusion Medicine, Brigham and Women’s Hospital, Harvard Medical School, 630E New Research Building, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
| | - Sean R. Stowell
- Joint Program in Transfusion Medicine, Brigham and Women’s Hospital, Harvard Medical School, 630E New Research Building, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
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Lopes-Marques M, Serrano C, Cardoso AR, Salazar R, Seixas S, Amorim A, Azevedo L, Prata MJ. GBA3: a polymorphic pseudogene in humans that experienced repeated gene loss during mammalian evolution. Sci Rep 2020; 10:11565. [PMID: 32665690 PMCID: PMC7360587 DOI: 10.1038/s41598-020-68106-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 06/03/2020] [Indexed: 11/18/2022] Open
Abstract
The gene encoding the cytosolic β-glucosidase GBA3 shows pseudogenization due to a truncated allele (rs358231) that is polymorphic in humans. Since this enzyme is involved in the transformation of many plant β-glycosides, this particular case of gene loss may have been influenced by dietary adaptations during evolution. In humans, apart from the inactivating allele, we found that GBA3 accumulated additional damaging mutations, implying an extensive GBA3 loss. The allelic distribution of loss-of-function alleles revealed significant differences between human populations which can be partially related with their staple diet. The analysis of mammalian orthologs disclosed that GBA3 underwent at least nine pseudogenization events. Most events of pseudogenization occurred in carnivorous lineages, suggesting a possible link to a β-glycoside poor diet. However, GBA3 was also lost in omnivorous and herbivorous species, hinting that the physiological role of GBA3 is not fully understood and other unknown causes may underlie GBA3 pseudogenization. Such possibility relies upon a putative role in sialic acid biology, where GBA3 participates in a cellular network involving NEU2 and CMAH. Overall, our data shows that the recurrent loss of GBA3 in mammals is likely to represent an evolutionary endpoint of the relaxation of selective constraints triggered by diet-related factors.
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Affiliation(s)
- Monica Lopes-Marques
- i3S- Instituto de Investigação e Inovação em Saúde, Population Genetics and Evolution Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
| | - Catarina Serrano
- i3S- Instituto de Investigação e Inovação em Saúde, Population Genetics and Evolution Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
| | - Ana R. Cardoso
- i3S- Instituto de Investigação e Inovação em Saúde, Population Genetics and Evolution Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
| | - Renato Salazar
- i3S- Instituto de Investigação e Inovação em Saúde, Population Genetics and Evolution Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
| | - Susana Seixas
- i3S- Instituto de Investigação e Inovação em Saúde, Population Genetics and Evolution Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
| | - António Amorim
- i3S- Instituto de Investigação e Inovação em Saúde, Population Genetics and Evolution Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
| | - Luisa Azevedo
- i3S- Instituto de Investigação e Inovação em Saúde, Population Genetics and Evolution Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
| | - Maria J. Prata
- i3S- Instituto de Investigação e Inovação em Saúde, Population Genetics and Evolution Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
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Kuchay RAH. New insights into the molecular basis of lactase non-persistence/persistence: a brief review. Drug Discov Ther 2020; 14:1-7. [PMID: 32101819 DOI: 10.5582/ddt.2019.01079] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Lactose, a disaccharide and main carbohydrate in milk, requires hydrolysis in the intestinal tract to release its monosaccharides galactose and glucose for use as energy source by enterocytes. This hydrolysis is catalyzed by the enzyme lactase, a β-galactosidase located in the brush border membrane of small intestinal enterocytes. In most mammals, lactase activity declines after the weaning, a condition known as lactase non-persistence (LNP). Lactase persistence (LP) is an autosomal dominant trait enabling the continued production of the enzyme lactase throughout adult life. Non-persistence or persistence of lactase expression into adult life being a polymorphic trait has been attributed to various single nucleotide polymorphisms in the enhancer region surrounding lactase gene (LCT). However, latest research has pointed to 'genetic-epigenetic interactions' as key to regulation of lactase expression. LNP and LP DNA haplotypes have demonstrated markedly different epigenetic aging as genetic factors contribute to gradual accumulation of epigenetic changes with age to affect lactase expression. This review will attempt to present an overview of latest insights into molecular basis of LNP/LP including the crucial role of 'genetic-epigenetic interactions' in regulating lactase expression.
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Pavlović M, Radlović N, Berenji K, Arsić B, Rokvić Ž. Lactose intolerance in children and adults. MEDICINSKI CASOPIS 2020; 54:105-112. [DOI: 10.5937/mckg54-26370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
Lactose is a disaccharide found in milk and dairy products. Children and adults with lactose intolerance are unable to tolerate significant amounts of lactose because of an inadequate amount of the enzyme lactase. The condition occurs in three main types: primary, secondary, and primary adult-type hypolactasia. The use of milk in the diet of these individuals may lead to appearance of the irritable bowel syndrome. In persons with lactose intolerance symptoms include diarrhoea, dominated by abdominal colic, loud peristaltic sounds, increased flatulence and meteorism. A diagnosis of lactose intolerance can usually be made with a careful history, elimination of lactose from the diet, lactose tolerance test, hydrogen breath test and genetic testing. In the absence of appropriate tests in patients with suspected primary adult-type hypolactasia, diagnosis can be made as in patients with food allergy. Treatment is based on the restriction of lactose intake with the use of fermented milk products. However, especially for children, if milk and dairy products are eliminated from the diet, it is important to ensure D vitamin and calcium supplementation.
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Di Costanzo M, Berni Canani R. Lactose Intolerance: Common Misunderstandings. ANNALS OF NUTRITION AND METABOLISM 2019; 73 Suppl 4:30-37. [DOI: 10.1159/000493669] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Lactose intolerance primarily refers to a syndrome having different symptoms upon the consumption of foods containing lactose. It is one of the most common form of food intolerance and occurs when lactase activity is reduced in the brush border of the small bowel mucosa. Individuals may be lactose intolerant to varying degrees, depending on the severity of these symptoms. When lactose is not digested, it can be fermented by gut microbiota leading to symptoms of lactose intolerance that include abdominal pain, bloating, flatulence, and diarrhea with a considerable intraindividual and interindividual variability in the severity of clinical manifestations. These gastrointestinal symptoms could be similar to cow’s milk allergy and could be wrongly labeled as symptoms of “milk allergy.” There are important differences between lactose intolerance and cow’s milk allergy; therefore, a better knowledge of these differences could limit misunderstandings in the diagnostic approach and in the management of these conditions.
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Stokes VJ, Nielsen MF, Hannan FM, Thakker RV. Hypercalcemic Disorders in Children. J Bone Miner Res 2017; 32:2157-2170. [PMID: 28914984 PMCID: PMC5703166 DOI: 10.1002/jbmr.3296] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 09/07/2017] [Accepted: 09/13/2017] [Indexed: 12/20/2022]
Abstract
Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)-dependent or PTH-independent, and may be congenital or acquired. PTH-independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH-dependent hypercalcemia. Acquired causes of PTH-independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH-independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH-dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH-dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 American Society for Bone and Mineral Research.
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Affiliation(s)
- Victoria J Stokes
- Academic Endocrine UnitRadcliffe Department of MedicineUniversity of OxfordOxfordUK
| | - Morten F Nielsen
- Academic Endocrine UnitRadcliffe Department of MedicineUniversity of OxfordOxfordUK
- Department of Clinical ResearchFaculty of HealthUniversity of Southern DenmarkOdenseDenmark
| | - Fadil M Hannan
- Academic Endocrine UnitRadcliffe Department of MedicineUniversity of OxfordOxfordUK
- Department of Musculoskeletal BiologyInstitute of Ageing and Chronic DiseaseUniversity of LiverpoolOxfordUK
| | - Rajesh V Thakker
- Academic Endocrine UnitRadcliffe Department of MedicineUniversity of OxfordOxfordUK
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Fazeli W, Kaczmarek S, Kirschstein M, Santer R. A novel mutation within the lactase gene (LCT): the first report of congenital lactase deficiency diagnosed in Central Europe. BMC Gastroenterol 2015. [PMID: 26215149 PMCID: PMC4515929 DOI: 10.1186/s12876-015-0316-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Background Congenital lactase deficiency is an extremely rare gastrointestinal disorder characterized by neonatal-onset watery diarrhoea and failure to thrive. We present the first genetically confirmed case of congenital lactase deficiency in Central Europe. Case presentation After an uneventful pregnancy and birth, a male newborn of consanguineous parents of Turkish origin presented with watery diarrhoea. On day 17, he was admitted to hospital with weight loss, hypertonic dehydration, and metabolic acidosis. Additionally, the patient showed an elevated calcium concentration in blood and urine as well as nephrocalcinosis. Diarrhoea stopped during intravenous rehydration and when feeding a glucose-, galactose-, and lactose-free formula. Therefore, glucose-galactose-malabsorption was assumed. However, genetic testing of the SGLT1 (SLC5A1) gene was negative and, indeed, feeding maltodextrine did not result in recurrence of diarrhoea. In contrast, lactose feeding immediately caused watery diarrhoea, suggesting congenital lactase deficiency. Genetic testing of the LCT gene revealed homozygosity for a 1-bp deletion in exon 8 (c.3448delT). Because of the nature of the mutation, causing a frame shift and a premature termination of translation, congenital lactase deficiency was confirmed and intestinal biopsies were unnecessary. The patient’s general condition improved substantially on a lactose-free diet, including hypercalcaemia, hypercalciuria, and nephrocalcinosis which, however, only disappeared after months. Conclusion This case demonstrates (a) that congenital lactase deficiency should be considered in cases of severe neonatal diarrhoea, (b) that intestinal biopsies can be avoided in typical cases that are confirmed by genetic testing, and (c) that the associated nephrocalcinosis can be reversed on diet and an appropriate fluid management.
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Affiliation(s)
- Walid Fazeli
- Department of Paediatrics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246, Hamburg, Germany.
| | - Sigrid Kaczmarek
- Department of Paediatrics, General Hospital Celle, Celle, Germany.
| | | | - René Santer
- Department of Paediatrics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246, Hamburg, Germany.
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Sala Coromina J, Vinaixa Vergés A, Garcia Puig R. Congenital lactase deficiency: Identification of a new mutation. ANALES DE PEDIATRÍA (ENGLISH EDITION) 2015. [DOI: 10.1016/j.anpede.2014.10.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Functional significance of single nucleotide polymorphisms in the lactase gene in diverse US patients and evidence for a novel lactase persistence allele at -13909 in those of European ancestry. J Pediatr Gastroenterol Nutr 2015; 60:182-91. [PMID: 25625576 PMCID: PMC4308731 DOI: 10.1097/mpg.0000000000000595] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Recent data from mainly homogeneous European and African populations implicate a 140-bp region 5' to the transcriptional start site of LCT (the lactase gene) as a regulatory site for lactase persistence and nonpersistence. Because there are no studies of US nonhomogeneous populations, we performed genotype/phenotype analysis of the -13910 and -22018 LCT single nucleotide polymorphisms (SNPs) in New England children, mostly of European ancestry. METHODS Duodenal biopsies were processed for disaccharidase activities, RNA quantification by reverse transcription polymerase chain reaction (RT-PCR), allelic expression ratios by PCR, and genotyping and SNP analysis. Results were compared with clinical information. RESULTS Lactase activity and mRNA levels, and sucrase-to-lactase ratios of enzyme activity and mRNA, showed robust correlations with genotype. None of the other LCT SNPs showed as strong a correlation with enzyme or mRNA levels as did -13910. Data were consistent, with the -13910 being the causal sequence variant instead of -22018. Four individuals heterozygous for -13910T/C had allelic expression patterns similar to individuals with -13910C/C genotypes; of these, 2 showed equal LCT expression from the 2 alleles and a novel variant (-13909C>A) associated with lactase persistence. CONCLUSIONS The identification of -13910C/C genotype is likely to predict lactase nonpersistence, consistent with prior published studies. A -13910T/T genotype will frequently, but not perfectly, predict lactase persistence in this mixed European-ancestry population; a -13910T/C genotype will not predict the phenotype. A long, rare haplotype in 2 individuals with -13910T/C genotype but equal allele-specific expression contains a novel lactase persistence allele present at -13909.
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12
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[Congenital lactase deficiency: Identification of a new mutation]. An Pediatr (Barc) 2014; 82:365-6. [PMID: 25468453 DOI: 10.1016/j.anpedi.2014.10.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 10/11/2014] [Accepted: 10/16/2014] [Indexed: 01/01/2023] Open
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Amiri M, Naim HY. Long term differential consequences of miglustat therapy on intestinal disaccharidases. J Inherit Metab Dis 2014; 37:929-37. [PMID: 24863482 DOI: 10.1007/s10545-014-9725-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Revised: 05/06/2014] [Accepted: 05/09/2014] [Indexed: 01/30/2023]
Abstract
Miglustat is an oral medication for treatment of lysosomal storage diseases such as Gaucher disease type I and Niemann Pick disease type C. In many cases application of Miglustat is associated with symptoms similar to those observed in intestinal carbohydrate malabsorption. Previously, we have demonstrated that intestinal disaccharidases are inhibited immediately by Miglustat in the intestinal lumen. Nevertheless, the multiple functions of Miglustat hypothesize long term effects of Miglustat on intracellular mechanisms, including glycosylation, maturation and trafficking of the intestinal disaccharidases. Our data show that a major long term effect of Miglustat is its interference with N-glycosylation of the proteins in the ER leading to a delay in the trafficking of sucrase-isomaltase. Also association with lipid rafts and plausibly apical targeting of this protein is partly affected in the presence of Miglustat. More drastic is the effect of Miglustat on lactase-phlorizin hydrolase which is partially blocked intracellularly. The de novo synthesized SI and LPH in the presence of Miglustat show reduced functional efficiencies according to altered posttranslational processing of these proteins. However, at physiological concentrations of Miglustat (≤50 μM) a major part of the activity of these disaccharidases is found to be still preserved, which puts the charge of the observed carbohydrate maldigestion mostly on the direct inhibition of disaccharidases in the intestinal lumen by Miglustat as the immediate side effect.
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Affiliation(s)
- Mahdi Amiri
- Department of Physiological Chemistry, University of Veterinary Medicine Hannover, D-30559, Hannover, Germany
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Greally MT, Robinson E, Allen NM, O'Donovan D, Crolla JA. De novo interstitial deletion 2q14.1q22.1: is there a recognizable phenotype? Am J Med Genet A 2014; 164A:3194-202. [PMID: 25263257 DOI: 10.1002/ajmg.a.36786] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 08/21/2014] [Indexed: 12/29/2022]
Abstract
In this report we describe a male patient with a rare de novo interstitial deletion of chromosome 2q14.1-q22.1. His karyotype was reported as 46,XY,del(2)(q13q21) but subsequent array comparative genomic hybridization (array CGH) analysis redefined the deletion breakpoints as 2q14.1 and 2q22.1. Eight patients have been reported with deletions either within or spanning the region 2q13 or 2q14 to 2q22.1. In five patients the diagnosis was made by karyotype analysis alone and in three reported patients and the proband array CGH analysis was also performed. When the proband was compared with the eight previously reported patients it was apparent that they shared many clinical findings suggesting that patients with a de novo interstitial deletion involving 2q13 or 2q14 to 2q21 or 2q22 may have a recognizable phenotype. There are 14 known disease-associated genes in the deleted region of 2q14.1-q22.1 and their possible phenotypic effects on the proband and the eight previously reported patients are discussed.
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Affiliation(s)
- Marie T Greally
- National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
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Sharma M, Rawal L, Panwar D, Sehgal N, Ali S. Differential expression of Homeobox C11 protein in water buffalo Bubalus bubalis and its putative 3D structure. BMC Genomics 2014; 15:638. [PMID: 25080327 PMCID: PMC4139611 DOI: 10.1186/1471-2164-15-638] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Accepted: 07/17/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The Homeobox (Hox) family complex contains 39 genes, clustered into four groups (A-D) all expressing in sequential manner. The HOX proteins are transcriptional factors involved in regulation of pattern formation of the anterio-posterior body axis across the species. Most of the Hox family genes have been studied with respect to their organization and expression during the embryonic stages. However, expression pattern of Homeobox C11 (Hoxc11) gene in the 5' region, particularly in higher mammals remains largely unexplored. RESULTS We cloned and expressed Homeobox C11 (Hoxc11) gene from water buffalo Bubalus bubalis. The recombinant HOXC11 protein expressed as inclusion bodies was solubilized in Tris buffer (10 mM, pH-6.5) and purified using Ni-NTA affinity column. The purity and molecular weight of HOXC11 protein (~33 kDa) were confirmed by SDS-PAGE and western blot analysis. Employing immunohistochemistry approach, we localized HOXC11 protein in the nuclei across the tissues of buffalo. Western blot analysis showed highest expression of HOXC11 protein in kidney and lung although its possible renal and respiratory roles are not yet established. Electrophoretic mobility shift assay (EMSA) demonstrated the specific binding of HOXC11 protein with the promoter element, CE-LPH1 of lactase-phlorizin hydrolase (LPH) gene showing reduced mobility of the protein-DNA complex, corroborating with earlier report on the possible role of this protein in intestinal functions. In silico analysis of HOXC11 showed predominance of α helices and presence of six conserved domains. We deduced the putative 3D structure of HOXC11 protein and fifteen possible DNA interacting residues within the homeodomain. CONCLUSIONS Present study augments our understanding on the specific expression of HOXC11 protein in kidney and lung in water buffalo. The fifteen DNA interacting residues reported herein provide an opportunity to establish much broader structural and functional perspectives of HOXC11 protein in the context of genome analysis in general and animal biotechnology in particular.
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Affiliation(s)
| | | | | | | | - Sher Ali
- Molecular Genetics Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
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16
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17
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Torniainen S, Freddara R, Routi T, Gijsbers C, Catassi C, Höglund P, Savilahti E, Järvelä I. Four novel mutations in the lactase gene (LCT) underlying congenital lactase deficiency (CLD). BMC Gastroenterol 2009; 9:8. [PMID: 19161632 PMCID: PMC2635369 DOI: 10.1186/1471-230x-9-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2008] [Accepted: 01/22/2009] [Indexed: 12/27/2022] Open
Abstract
Background Congenital lactase deficiency (CLD) is a severe gastrointestinal disorder of newborns. The diagnosis is challenging and based on clinical symptoms and low lactase activity in intestinal biopsy specimens. The disease is enriched in Finland but is also present in other parts of the world. Mutations encoding the lactase (LCT) gene have recently been shown to underlie CLD. The purpose of this study was to identify new mutations underlying CLD in patients with different ethnic origins, and to increase awareness of this disease so that the patients could be sought out and treated correctly. Methods Disaccharidase activities in intestinal biopsy specimens were assayed and the coding region of LCT was sequenced from five patients from Europe with clinical features compatible with CLD. In the analysis and prediction of mutations the following programs: ClustalW, Blosum62, PolyPhen, SIFT and Panther PSEC were used. Results Four novel mutations in the LCT gene were identified. A single nucleotide substitution leading to an amino acid change S688P in exon 7 and E1612X in exon 12 were present in a patient of Italian origin. Five base deletion V565fsX567 leading to a stop codon in exon 6 was found in one and a substitution R1587H in exon 12 from another Finnish patient. Both Finnish patients were heterozygous for the Finnish founder mutation Y1390X. The previously reported mutation G1363S was found in a homozygous state in two siblings of Turkish origin. Conclusion This is the first report of CLD mutations in patients living outside Finland. It seems that disease is more common than previously thought. All mutations in the LCT gene lead to a similar phenotype despite the location and/or type of mutation.
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Affiliation(s)
- Suvi Torniainen
- Department of Medical Genetics, University of Helsinki, Haartman Institute, Helsinki, Finland.
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18
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Abstract
Lactase non-persistence (adult-type hypolactasia) is present in more than half of the human population and is caused by the down-regulation of lactase enzyme activity during childhood. Congenital lactase deficiency (CLD) is a rare severe gastrointestinal disorder of new-borns enriched in the Finnish population. Both lactase deficiencies are autosomal recessive traits and characterized by diminished expression of lactase activity in the intestine. Genetic variants underlying both forms have been identified. Here we review the current understanding of the molecular defects of human lactase deficiencies and their phenotype-genotype correlation, the implications on clinical practice, and the understanding of their function and role in human evolution.
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Affiliation(s)
- Irma Järvelä
- Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
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19
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Abstract
Food intolerance is an adverse reaction to a particular food or ingredient that may or may not be related to the immune system. A deficiency in digestive enzymes can also cause some types of food intolerances like lactose and gluten intolerance. Food intolerances may cause unpleasant symptoms, including nausea, bloating, abdominal pain, and diarrhea, which usually begin about half an hour after eating or drinking the food in question, but sometimes symptoms may delayed up to 48 h. There is also a strong genetic pattern to food intolerances. Intolerance reactions to food chemicals are mostly dose-related, but also some people are more sensitive than others. Diagnosis can include elimination and challenge testing. Food intolerance can be managed simply by avoiding the particular food from entering the diet. Babies or younger children with lactose intolerance can be given soy milk or hypoallergenic milk formula instead of cow's milk. Adults may be able to tolerate small amounts of troublesome foods, so may need to experiment. Eosinophilic esophagitis (EE) is defined as isolated eosinophilic infiltration in patients with reflux-like symptoms and normal pH studies and whose symptoms are refractory to acid-inhibition therapy. Food allergy, abnormal immunologic response, and autoimmune mechanisms are suggested as possible etiological factors for EE. This article is intended to review the current literature and to present a practical approach for managing food intolerances and EE in childhood.
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Robayo-Torres CC, Nichols BL. Molecular Differentiation of Congenital Lactase Deficiency from Adult-Type Hypolactasia. Nutr Rev 2008; 65:95-8. [PMID: 17345962 DOI: 10.1111/j.1753-4887.2007.tb00286.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
A limited fraction of the human adult population retains intestinal lactase-phlorizin hydrolase (LPH) activity during adulthood, and this is called the lactase persistence phenotype. However, 95% of all adults have adult-type hypolactasia (ATH) and have difficulty digesting milk sugar. Rarely, some infants are born with an inability to digest lactase (congenital lactase deficiency or CLD) due to low levels of LPH activity, which results in severe clinical consequences if not properly diagnosed and treated by lactose avoidance. Recently, it has been shown that both recessive LPH deficiencies, CLD and ATH, are related to DNA variants affecting the lactase (LCT) gene, but they are mediated through very different molecular mechanisms. The LCT mutations resulting in childhood CLD lead to low LPH activity through nonsense-mediated LCT mRNA decay, whereas the critical nucleotide variants for the ATH phenotype represent distal enhancer polymorphisms, which regulate developmentally LCT transcript levels in intestinal cells.
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Affiliation(s)
- Claudia C Robayo-Torres
- Department of Pediatrics, Baylor College of Medicine, 1100 Bates St., Houston, TX 77030, USA
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21
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Rasinpera H, Saarinen K, Pelkonen A, Jarvela I, Savilahti E, Kolho KL. Molecularly defined adult-type hypolactasia in school-aged children with a previous history of cow’s milk allergy. World J Gastroenterol 2006; 12:2264-8. [PMID: 16610034 PMCID: PMC4087659 DOI: 10.3748/wjg.v12.i14.2264] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the role of lactase non-persistence/persistence in school-aged children and their milk-related symptoms.
METHODS: The genotypes for the C/T-13910 variant associated with lactase non-persistence/ persistence were determined using PCR-minisequencing in a group of 172 children with a mean age of 8.6 years (SE = 0.02, 93 boys) participating in a follow-up study for cow’s milk allergy. The parents were asked to assess their children’s milk consumption and abdominal symptoms.
RESULTS: The presence of allergy to cow’s milk was not associated with the C/C-13910 genotype related with a decline of lactase enzyme activity during childhood (lactase non-persistence). The frequency of the C/C-13910 genotype (16%) was similar to published figures for the prevalence of adult-type hypolactasia in Finland. The majority of the children (90%) in this series consumed milk but 26% of their families suspected that their children had milk-related symptoms. Forty-eight percent of the children with the C/C-13910 genotype did not drink milk at all or consumed a low lactose containing diet prior to the genotyping (P < 0.004 when compared to the other genotypes).
CONCLUSION: Analysis of the C/T-13910 polymorphism is an easy and reliable method for excluding adult-type hypolactasia in children with milk-related symptoms. Genotyping for this variant can be used to advise diets for children with a previous history of cow’s milk allergy.
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Affiliation(s)
- Heli Rasinpera
- Department of Medical Genetics, University of Helsinki, Finland
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22
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Kuokkanen M, Kokkonen J, Enattah NS, Ylisaukko-oja T, Komu H, Varilo T, Peltonen L, Savilahti E, Järvelä I. Mutations in the translated region of the lactase gene (LCT) underlie congenital lactase deficiency. Am J Hum Genet 2006; 78:339-44. [PMID: 16400612 PMCID: PMC1380240 DOI: 10.1086/500053] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2005] [Accepted: 11/22/2005] [Indexed: 12/14/2022] Open
Abstract
Congenital lactase deficiency (CLD) is a severe gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. We initially assigned the CLD locus by linkage and linkage disequilibrium on 2q21 in 19 Finnish families. Here we report the molecular background of CLD via characterization of five distinct mutations in the coding region of the lactase (LCT) gene. Twenty-seven patients out of 32 (84%) were homozygous for a nonsense mutation, c.4170T-->A (Y1390X), designated "Fin(major)." Four rare mutations--two that result in a predicted frameshift and early truncation at S1666fsX1722 and S218fsX224 and two point mutations that result in substitutions Q268H and G1363S of the 1,927-aa polypeptide--confirmed the lactase mutations as causative for CLD. These findings facilitate genetic testing in clinical practice and enable genetic counseling for this severe disease. Further, our data demonstrate that, in contrast to common adult-type hypolactasia (lactose intolerance) caused by a variant of the regulatory element, the severe infancy form represents the outcome of mutations affecting the structure of the protein inactivating the enzyme.
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Affiliation(s)
- Mikko Kuokkanen
- Department of Molecular Medicine, National Public Health Institute, Department of Medical Genetics and Hospital for Children and Adolescents, University of Helsinki, and Helsinki University Central Hospital, Laboratory Services HUSLAB, Laboratory of Molecular Genetics, Helsinki; Department of Paediatrics, Oulu University Hospital, Oulu, Finland; and Broad Institute of MIT and Harvard, Boston
| | - Jorma Kokkonen
- Department of Molecular Medicine, National Public Health Institute, Department of Medical Genetics and Hospital for Children and Adolescents, University of Helsinki, and Helsinki University Central Hospital, Laboratory Services HUSLAB, Laboratory of Molecular Genetics, Helsinki; Department of Paediatrics, Oulu University Hospital, Oulu, Finland; and Broad Institute of MIT and Harvard, Boston
| | - Nabil Sabri Enattah
- Department of Molecular Medicine, National Public Health Institute, Department of Medical Genetics and Hospital for Children and Adolescents, University of Helsinki, and Helsinki University Central Hospital, Laboratory Services HUSLAB, Laboratory of Molecular Genetics, Helsinki; Department of Paediatrics, Oulu University Hospital, Oulu, Finland; and Broad Institute of MIT and Harvard, Boston
| | - Tero Ylisaukko-oja
- Department of Molecular Medicine, National Public Health Institute, Department of Medical Genetics and Hospital for Children and Adolescents, University of Helsinki, and Helsinki University Central Hospital, Laboratory Services HUSLAB, Laboratory of Molecular Genetics, Helsinki; Department of Paediatrics, Oulu University Hospital, Oulu, Finland; and Broad Institute of MIT and Harvard, Boston
| | - Hanna Komu
- Department of Molecular Medicine, National Public Health Institute, Department of Medical Genetics and Hospital for Children and Adolescents, University of Helsinki, and Helsinki University Central Hospital, Laboratory Services HUSLAB, Laboratory of Molecular Genetics, Helsinki; Department of Paediatrics, Oulu University Hospital, Oulu, Finland; and Broad Institute of MIT and Harvard, Boston
| | - Teppo Varilo
- Department of Molecular Medicine, National Public Health Institute, Department of Medical Genetics and Hospital for Children and Adolescents, University of Helsinki, and Helsinki University Central Hospital, Laboratory Services HUSLAB, Laboratory of Molecular Genetics, Helsinki; Department of Paediatrics, Oulu University Hospital, Oulu, Finland; and Broad Institute of MIT and Harvard, Boston
| | - Leena Peltonen
- Department of Molecular Medicine, National Public Health Institute, Department of Medical Genetics and Hospital for Children and Adolescents, University of Helsinki, and Helsinki University Central Hospital, Laboratory Services HUSLAB, Laboratory of Molecular Genetics, Helsinki; Department of Paediatrics, Oulu University Hospital, Oulu, Finland; and Broad Institute of MIT and Harvard, Boston
| | - Erkki Savilahti
- Department of Molecular Medicine, National Public Health Institute, Department of Medical Genetics and Hospital for Children and Adolescents, University of Helsinki, and Helsinki University Central Hospital, Laboratory Services HUSLAB, Laboratory of Molecular Genetics, Helsinki; Department of Paediatrics, Oulu University Hospital, Oulu, Finland; and Broad Institute of MIT and Harvard, Boston
| | - Irma Järvelä
- Department of Molecular Medicine, National Public Health Institute, Department of Medical Genetics and Hospital for Children and Adolescents, University of Helsinki, and Helsinki University Central Hospital, Laboratory Services HUSLAB, Laboratory of Molecular Genetics, Helsinki; Department of Paediatrics, Oulu University Hospital, Oulu, Finland; and Broad Institute of MIT and Harvard, Boston
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23
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Abstract
Adult-type hypolactasia (lactase non-persistence; primary lactose malabsorption) is characterized by the down-regulation of the lactase enzyme activity in the intestinal wall after weaning. The down-regulation is genetically determined and a mutation has occurred that has made part of mankind tolerate milk (lactase persistence). A DNA-variant, single nucleotide polymorphism C/T-13910 located 13 910 base pairs (bp) upstream of the lactase gene (LCT) at chromosome 2q21-22 has been shown to associate with the lactase persistence/non-persistence trait both in family and case-control studies. The C/T-13910 variant is located in a non-coding region in the genome in intron 13 of the minichromosome maintenance type 6 gene (MCM6). Significant correlation between the C/T-13910-variant and lactase activity in the intestinal biopsy specimens has been demonstrated. Molecular epidemiological studies on the prevalence of the C/C-13910 genotype associated with low lactase activity are in agreement with the prevalence figures for adult type hypolactasia in>70 diverse ethnic groups studied. Recent functional studies have suggested that this variant has an enhancer effect over the lactase gene. Based on the biochemical, functional, genetic and molecular epidemiological studies of the C/T-13910 variant, genetic testing for adult type hypolactasia has been introduced into clinical practice in Finland. Identification of the genetic change has highlighted the role of non-coding variants in the regulation of common genes and created new tools to study the mechanism of lactase enzyme activation.
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Affiliation(s)
- Irma E Järvelä
- Laboratory of Molecular Genetics, Helsinki University Central Hospital, Finland.
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24
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Sibley E. Genetic variation and lactose intolerance: detection methods and clinical implications. ACTA ACUST UNITED AC 2004; 4:239-45. [PMID: 15287817 DOI: 10.2165/00129785-200404040-00003] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The maturational decline in lactase activity renders most of the world's adult human population intolerant of excessive consumption of milk and other dairy products. In conditions of primary or secondary lactase deficiency, the lactose sugars in milk pass through the gastrointestinal tract undigested or are partially digested by enzymes produced by intestinal bacterial flora to yield short chain fatty acids, hydrogen, carbon dioxide, and methane. The undigested lactose molecules and products of bacterial digestion can result in symptoms of lactose intolerance, diarrhea, gas bloat, flatulence, and abdominal pain. Diagnosis of lactose intolerance is often made on clinical grounds and response to an empiric trail of dietary lactose avoidance. Biochemical methods for assessing lactose malabsorption in the form of the lactose breath hydrogen test and direct lactase enzyme activity performed on small intestinal tissue biopsy samples may also be utilized. In some adults, however, high levels of lactase activity persist into adulthood. This hereditary persistence of lactase is common primarily in people of northern European descent and is attributed to inheritance of an autosomal-dominant mutation that prevents the maturational decline in lactase expression. Recent reports have identified genetic polymorphisms that are closely associated with lactase persistence and nonpersistence phenotypes. The identification of genetic variants associated with lactase persistence or nonpersistence allows for molecular detection of the genetic predisposition towards adult-onset hypolactasia by DNA sequencing or restriction fragment length polymorphism analysis. The role for such genetic detection in clinical practice seems limited to ruling out adult-onset hypolactasia as a cause of intolerance symptoms but remains to be fully defined. Attention should be paid to appropriate interpretation of genetic detection in order to avoid potentially harmful reduction in dairy intake or misdiagnosis of secondary lactase deficiency.
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Affiliation(s)
- Eric Sibley
- Division of Pediatric Gastroenterology, Stanford University School of Medicine, Stanford, California 94304, USA.
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25
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Rasinperä H, Savilahti E, Enattah NS, Kuokkanen M, Tötterman N, Lindahl H, Järvelä I, Kolho KL. A genetic test which can be used to diagnose adult-type hypolactasia in children. Gut 2004; 53:1571-6. [PMID: 15479673 PMCID: PMC1774274 DOI: 10.1136/gut.2004.040048] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2004] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIMS Adult-type hypolactasia (primary lactose malabsorption) affects most of world's human population and limits the use of fresh milk due to lactose intolerance. The diagnosis of adult-type hypolactasia has been difficult to establish because of unsatisfactory diagnostic methods. C/T(-13910) single nucleotide polymorphism residing 13910 base pairs from the 5' end of the lactase gene has been shown to be associated with lactase persistence. The aim of the study was to assess the applicability of the C/T(-13910) variant as a diagnostic test for adult-type hypolactasia during childhood. METHODS Intestinal biopsies were obtained from 329 children and adolescents of African, Finnish, and other White origins aged 0.1-20 years undergoing upper gastrointestinal endoscopy because of abdominal complaints. The biopsies were assayed for lactase, sucrase, and maltase activity and genotyped for the C/T(-13910) variant using polymerase chain reaction minisequencing. RESULTS The frequency of the C/C(-13910) genotype defining lactase non-persistence was well in agreement in this study with published figures for the prevalences of adult-type hypolactasia in Africans and Whites. The C/C(-13910) genotype was associated with very low lactase activity (<10 U/g protein) in the majority of children tested at 8 years of age and in every child older than 12 years of age giving a specificity of 100% and sensitivity of 93% for the genetic test. The decline of lactase activity was somewhat earlier in African compared with Finnish children with C/C(-13910) genotype (p<0.03). CONCLUSIONS Genetic test of C/T(-13910) polymorphism can be used as a first stage screening test for adult-type hypolactasia.
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Affiliation(s)
- H Rasinperä
- HospGenetics, University of Helsinki, Finland
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26
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Abstract
PURPOSE OF REVIEW The small intestinal mucosa is highly specialized for terminal digestion of nutrient polysaccharides and disaccharides and absorption of monosaccharides. However, in the case of digestive or absorptive deficiency, symptoms of carbohydrate intolerance result. Significant progress has been made toward defining the molecular genetic mechanisms responsible for several carbohydrate intolerances. RECENT FINDINGS This review summarizes monosaccharide and disaccharide intolerance conditions and recent clinical and basic science reports related to carbohydrate digestion and membrane transport. Genetic polymorphisms closely associated with lactase persistence/nonpersistence have been identified. Lactose intolerance is capable of preventing the achievement of adequate peak bone mass in susceptible young adults and may predispose to osteoporosis. Recent studies support previous reports that fructose malabsorption is associated with unexplained gastrointestinal symptoms. GLUT2 may be recruited from the basolateral to the apical membrane of enterocytes to facilitate small intestinal fructose absorption. SUMMARY Knowledge regarding the clinical aspects of and the physiologic mechanisms responsible for specific carbohydrate intolerances has allowed for improved diagnostic and treatment options and has contributed to continuing investigation of intestinal gene expression.
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Affiliation(s)
- Eric Sibley
- Stanford University School of Medicine, Stanford, California 94304, USA.
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27
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Abstract
The enzyme lactase that is located in the villus enterocytes of the small intestine is responsible for digestion of lactose in milk. Lactase activity is high and vital during infancy, but in most mammals, including most humans, lactase activity declines after the weaning phase. In other healthy humans, lactase activity persists at a high level throughout adult life, enabling them to digest lactose as adults. This dominantly inherited genetic trait is known as lactase persistence. The distribution of these different lactase phenotypes in human populations is highly variable and is controlled by a polymorphic element cis-acting to the lactase gene. A putative causal nucleotide change has been identified and occurs on the background of a very extended haplotype that is frequent in Northern Europeans, where lactase persistence is frequent. This single nucleotide polymorphism is located 14 kb upstream from the start of transcription of lactase in an intron of the adjacent gene MCM6. This change does not, however, explain all the variation in lactase expression.
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Affiliation(s)
- Dallas M Swallow
- Galton Laboratory, Department of Biology, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, England.
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28
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Affiliation(s)
- Tuomo Rankinen
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA.
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29
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Poulter M, Hollox E, Harvey CB, Mulcare C, Peuhkuri K, Kajander K, Sarner M, Korpela R, Swallow DM. The causal element for the lactase persistence/non-persistence polymorphism is located in a 1 Mb region of linkage disequilibrium in Europeans. Ann Hum Genet 2003; 67:298-311. [PMID: 12914565 DOI: 10.1046/j.1469-1809.2003.00048.x] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Expression of lactase in the intestine persists into adult life in some people and not others, and this is due to a cis-acting regulatory polymorphism. Previous data indicated that a mutation leading to lactase persistence had occurred on the background of a 60 kb 11-site LCT haplotype known as A (Hollox et al. 2001). Recent studies reported a 100% correlation of lactase persistence with the presence of the T allele at a CT SNP at -14 kb from LCT, in individuals of Finnish origin, suggesting that this SNP may be causal of the lactase persistence polymorphism, and also reported a very tight association with a second SNP (GA -22 kb) (Enattah et al. 2002). Here we report the existence of a one megabase stretch of linkage disequilibrium in the region of LCT and show that the -14 kb T allele and the -22 kb A allele both occur on the background of a very extended A haplotype. In a series of Finnish individuals we found a strong correlation (40/41 people) with lactose digestion and the presence of the T allele. The T allele was present in all 36 lactase persistent individuals from the UK (phenotyped by enzyme assay) studied, 31/36 of whom were of Northern European ancestry, but not in 11 non-persistent individuals who were mainly of non-UK ancestry. However, the CT heterozygotes did not show intermediate lactase enzyme activity, unlike those previously phenotyped by determining allelic transcript expression. Furthermore the one lactase persistent homozygote identified by having equally high expression of A and B haplotype transcripts, was heterozygous for CT at the -14 kb site. SNP analysis across the 1 megabase region in this person showed no evidence of recombination on either chromosome between the -14 kb SNP and LCT. The combined data shows that although the -14 kb CT SNP is an excellent candidate for the cause of the lactase persistence polymorphism, linkage disequilibrium extends far beyond the region searched so far. In addition, the CT SNP does not, on its own, explain all the variation in expression of LCT, suggesting the possibility of genetic heterogeneity.
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Affiliation(s)
- M Poulter
- The Galton Laboratory, Department of Biology, Wolfson House, University College London, 4 Stephenson Way, London NW1 2HE, UK
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30
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Affiliation(s)
- R J Grand
- Division of Gastroenterology, Children's Hospital Boston, MA 02115, USA.
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31
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Norio R. The Finnish Disease Heritage III: the individual diseases. Hum Genet 2003; 112:470-526. [PMID: 12627297 DOI: 10.1007/s00439-002-0877-1] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2002] [Accepted: 10/30/2002] [Indexed: 02/03/2023]
Abstract
This article is the third and last in a series entitled The Finnish Disease Heritage I-III. All the 36 rare hereditary diseases belonging to this entity are described for clinical and molecular genetic purposes, based on the Finnish experience gathered over a period of half a century. In addition, five other diseases are mentioned. They may be included in the list of the "Finnish diseases" after adequate complementary studies.
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Affiliation(s)
- Reijo Norio
- Department of Medical Genetics, The Family Federation of Finland, Helsinki, Finland.
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32
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Nichols BL, Avery SE, Karnsakul W, Jahoor F, Sen P, Swallow DM, Luginbuehl U, Hahn D, Sterchi EE. Congenital maltase-glucoamylase deficiency associated with lactase and sucrase deficiencies. J Pediatr Gastroenterol Nutr 2002; 35:573-9. [PMID: 12394387 DOI: 10.1097/00005176-200210000-00022] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Multiple enzyme deficiencies have been reported in some cases of congenital glucoamylase, sucrase, or lactase deficiency. Here we describe such a case and the investigations that we have made to determine the cause of this deficiency. METHODS AND RESULTS A 2.5 month-old infant, admitted with congenital lactase deficiency, failed to gain weight on a glucose oligomer formula (Nutramigen). Jejunal mucosal biopsy at 4 and 12 months revealed normal histology with decreased maltase-glucoamylase, sucrase-isomaltase, and lactase-phlorizin hydrolase activities. Testing with a C-starch/breath CO loading test confirmed proximal starch malabsorption. Sequencing of maltase-glucoamylase cDNA revealed homozygosity for a nucleotide change (C1673T) in the infant, which causes an amino acid substitution (S542L) 12 amino acids after the N-terminal catalytic aspartic acid. The introduction of this mutation into "wildtype" N-terminus maltase-glucoamylase cDNA was not associated with obvious loss of maltase-glucoamylase enzyme activities when expressed in COS 1 cells and this amino-acid change was subsequently found in other people. Sequencing of the promoter region revealed no nucleotide changes. Maltase-glucoamylase, lactase, and sucrase-isomaltase were each normally synthesized and processed in organ culture. CONCLUSIONS The lack of evidence for a causal nucleotide change in the maltase-glucoamylase gene in this patient, and the concomitant low levels of lactase and sucrase activity, suggest that the depletion of mucosal maltase-glucoamylase activity and starch digestion was caused by shared, pleiotropic regulatory factors.
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Affiliation(s)
- Buford L Nichols
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
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33
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Abstract
Genetic isolates, as shown empirically by the Finnish, Old Order Amish, Hutterites, Sardinian and Jewish communities among others, represent a most important and powerful tool in genetically mapping inherited disorders. The main features associated with that genetic power are the existence of multigenerational pedigrees which are mostly descended from a small number of founders a short number of generations ago, environmental and phenotypic homogeneity, restricted geographical distribution, the presence of exhaustive and detailed records correlating individuals in very well ascertained pedigrees, and inbreeding as a norm. On the other hand, the presence of a multifounder effect or admixture among divergent populations in the founder time (e.g. the Finnish and the Paisa community from Colombia) will theoretically result in increased linkage disequilibrium among adjacent loci. The present review evaluates the historical context and features of some genetic isolates with emphasis on the basic population genetic concepts of inbreeding and genetic drift, and also the state-of-the-art in mapping traits, both Mendelian and complex, on genetic isolates.
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Affiliation(s)
- M Arcos-Burgos
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852, USA
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Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I. Identification of a variant associated with adult-type hypolactasia. Nat Genet 2002; 30:233-7. [PMID: 11788828 DOI: 10.1038/ng826] [Citation(s) in RCA: 671] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Adult-type hypolactasia, also known as lactase non-persistence (lactose intolerance), is a common autosomal recessive condition resulting from the physiological decline in activity of the lactase-phlorizin hydrolase (LPH) in intestinal cells after weaning. LPH hydrolyzes lactose into glucose and galactose. Sequence analyses of the coding and promoter regions of LCT, the gene encoding LPH, has revealed no DNA variations correlating with lactase non-persistence. An associated haplotype spanning LCT, as well as a distinct difference in the transcript levels of 'non-persistence' and 'persistence' alleles in heterozygotes, suggest that a cis-acting element contributes to the lactase non-persistence phenotype. Using linkage disequilibrium (LD) and haplotype analysis of nine extended Finnish families, we restricted the locus to a 47-kb interval on 2q21. Sequence analysis of the complete region and subsequent association analyses revealed that a DNA variant, C/T-13910, roughly 14 kb upstream from the LCT locus, completely associates with biochemically verified lactase non-persistence in Finnish families and a sample set of 236 individuals from four different populations. A second variant, G/A-22018, 8 kb telomeric to C/T-13910, is also associated with the trait in 229 of 236 cases. Prevalence of the C/T-13910 variant in 1,047 DNA samples is consistent with the reported prevalence of adult-type hypolactasia in four different populations. That the variant (C/T-13910) occurs in distantly related populations indicates that it is very old.
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Affiliation(s)
- Nabil Sabri Enattah
- Department of Molecular Medicine, National Public Health Institute, Haartmaninkatu 8, PO Box 104, FIN-00251 Helsinki, Finland
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Montagnani M, Love MW, Rössel P, Dawson PA, Qvist P. Absence of dysfunctional ileal sodium-bile acid cotransporter gene mutations in patients with adult-onset idiopathic bile acid malabsorption. Scand J Gastroenterol 2001; 36:1077-80. [PMID: 11589382 DOI: 10.1080/003655201750422693] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND A congenital form of idiopathic intestinal bile acid malabsorption (IBAM) has been associated with dysfunctional mutations in the ileal apical sodium-dependent bile acid transporter (ASBT). The aim of this study was to determine whether mutations in the ASBT gene (SLC10A2) predispose to the development of adult-onset idiopathic bile acid malabsorption and chronic watery diarrhea. METHODS Genomic DNA was obtained from 13 adult IBAM patients previously diagnosed on the basis of clinical data, response to cholestyramine, and abnormal 75Se-homocholic acid taurine (SeHCAT) test values. The ASBT gene was screened for the presence of mutations or polymorphisms by single-stranded conformation polymorphism analysis (SSCP) and DNA sequencing. RESULTS ASBT gene polymorphisms were detected in 5 of the 13 adult IBAM patients. Four patients were heterozygous for a common polymorphism in exon 3, leading to an alanine to serine substitution at codon 171 (A171S). An additional subject was heterozygous for a polymorphism in exon 1 that causes a valine to isoleucine substitution at codon 98 (V981). These functional polymorphisms were also found in unaffected subjects and do not appear to affect ASBT function. CONCLUSIONS Adult-onset IBAM is not directly related to dysfunctional mutations in the coding region or intron/exon junctions of the SLC10A2 gene. In the absence of apparent ileal disease or intestinal motility defects, inappropriate down-regulation of the ileal bile acid transporter or defects in ileocyte transfer of bile acids into the portal circulation could explain this form of adult IBAM.
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Affiliation(s)
- M Montagnani
- Dept. of Internal Medicine and Gastroenterology, University of Bologna, Policlinico S. Orsola, Italy
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Abstract
Lactose intolerance affects hundreds of millions of people worldwide. Although the presentation is frequently atypical, it should be part of the differential diagnosis when evaluating nonspecific gastrointestinal symptoms. We review the terminology, types of lactase deficiencies, diagnostic procedures, and management.
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Affiliation(s)
- Y T Patel
- Division of Gastroenterology, Southern Illinois University School of Medicine, 701 North 1st Street, Room D123, Springfield, IL 62781, USA
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Abstract
Lactose maldigestion has been under intensive research since its discovery in the 1960's. We know the prevalence of lactose maldigestion in a great number of countries and ethnic groups. However, there is often no provision made for the secondary type of maldigestion, and the study populations have sometimes been selected rather than picked at random. New methods for the measurement of lactose digestion have been developed, and its genetic mechanisms have received a great deal of attention during the last few years. However, in many studies the measurement and/or reporting of symptoms has quite often been overlooked. In this review, various topics related to lactose intolerance are discussed with a special emphasis on its symptoms.
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Affiliation(s)
- T H Vesa
- Foundation for Nutrition Research, Helsinki, Finland
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Abstract
Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of disease genes. Specific rare, monogenic diseases become enriched, and families with multiple affected individuals occur frequently enough to be used in linkage analyses for locus identification. Further, the vast majority of cases are caused by the same mutation, and disease alleles reveal linkage disequilibrium (LD) with markers over significant genetic intervals; this facilitates disease locus identification by similarity search for a shared genotype or haplotype in small study samples consisting of few affected individuals. LD observed in disease alleles adds power to linkage analyses and helps to define the exact location of disease loci on the genetic map. Typically, based on the linkage disequilibrium and the ancient haplotype, the critical DNA region can be defined from the original 1- to 2-cM resolution obtained in linkage analysis to 50-200 kb, greatly facilitating the targeting of physical cloning and sequencing efforts. These advantages have been well demonstrated in the positional cloning of several rare monogenic diseases enriched in population isolates like the example of Finland used here. How useful genetic isolates will prove to be in the identification of complex disease genes is dependent on the genealogical history of the isolate, including the size of the founding population and the expansion rate during the history of the population.
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Affiliation(s)
- L Peltonen
- Department of Human Genetics, UCLA School of Medicine, Los Angeles, CA 90095-7088, USA.
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