• Cell biology
• Chaperones
• Genetic diseases
• Genetics

• Humans
• Myosin Type II/metabolism
• Myosin Type II/genetics
• Molecular Chaperones/metabolism
• Molecular Chaperones/genetics
• Mutation, Missense
• Fibroblasts/metabolism
• Male
• Malabsorption Syndromes/genetics
• Malabsorption Syndromes/metabolism
• Malabsorption Syndromes/pathology
• Female
• Microvilli/pathology
• Mucolipidoses
• Intracellular Signaling Peptides and Proteins

• Oesterreichische Nationalbank

• actin
• confocal microscopy
• congenital diarrhea
• intestinal epithelium
• intracellular trafficking
• microvilli
• myosin

• R01 DK048370 NIDDK NIH HHS
• R01 DK111949 NIDDK NIH HHS
• R01 DK095811 NIDDK NIH HHS
• IK2 BX004885 BLRD VA
• RC2 DK118640 NIDDK NIH HHS
• R01 DK125546 NIDDK NIH HHS

• CODE
• cholestasis
• congenital
• diarrhea
• gene therapy
• pediatric acute liver failure

• Humans
• Liver Diseases/metabolism
• Liver Diseases/genetics
• Animals
• Protein Transport
• Endoplasmic Reticulum/metabolism
• Mucolipidoses/metabolism
• Mucolipidoses/genetics
• trans-Golgi Network/metabolism
• Malabsorption Syndromes
• Microvilli/pathology

• Animals
• Humans
• Disease Models, Animal
• Enterocytes/metabolism
• Enterocytes/pathology
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Intestinal Diseases/genetics
• Intestinal Diseases/pathology
• Intestinal Diseases/metabolism
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/pathology
• Models, Biological
• Diarrhea/metabolism
• Diarrhea/pathology

• R01 DK048370 NIDDK NIH HHS
• P30 DK058404 NIDDK NIH HHS
• RC2 DK118640 NIDDK NIH HHS
• P30 DK034854 NIDDK NIH HHS
• RC2DK118640 NIDDK NIH HHS
• R01 DK128190 NIDDK NIH HHS
• National Institute of Diabetes and Digestive and Kidney Diseases
• TKO Foundation
• Boston Children’s Hospital
• Christine Volpe Fund

• children
• enteral autonomy
• food
• formula
• neonatal diarrhea
• nutrition
• parenteral nutrition
• treatment
• tube feeding
• weaning

• Humans
• Enteral Nutrition/methods
• Diarrhea/diet therapy
• Diarrhea/therapy
• Infant
• Parenteral Nutrition/methods
• Intestinal Diseases/diet therapy
• Intestinal Diseases/therapy
• Infant, Newborn
• Dietary Supplements
• Diarrhea, Infantile/diet therapy
• Diarrhea, Infantile/therapy

• RC2 DK118640 NIDDK NIH HHS
• T32 GM008243 NIGMS NIH HHS

• Myosin 5c
• immunohistochemistry
• molecular docking
• pentabromopseudilin
• tropomyosin

• MVID
• MYO5B
• MYO5B deficiency
• PFIC10
• cholestasis
• malabsorption
• microvillus inclusion disease

• Humans
• Mucolipidoses/genetics
• Mucolipidoses/pathology
• Microvilli/pathology
• Microvilli/genetics
• Malabsorption Syndromes/genetics
• Malabsorption Syndromes/pathology
• Phenotype
• Animals
• Myosin Type V/genetics
• Myosin Type V/metabolism
• Mutation
• Genetic Predisposition to Disease

• Antimicrobial peptide
• Attractive physical form
• Blood cells
• Gastrointestinal tract
• In vivo tissue-penetrating biomaterial
• Oral drug delivery

• Peptides/chemistry
• Peptides/pharmacology
• Anti-Bacterial Agents/chemistry
• Anti-Bacterial Agents/pharmacology
• Administration, Oral
• Powders/chemistry
• Catfishes
• Animals
• Particle Size
• Hydrogen-Ion Concentration

• Liver
• MYO5B
• cholestasis
• compound heterozygous mutations
• pathology
• pruritus

• Congenital diarrhea
• MVID
• MYO5B
• Microvillus inclusion disease
• Myosin VB
• animal models
• enteroids

• Animals
• Diarrhea/metabolism
• Humans
• Malabsorption Syndromes
• Microvilli/metabolism
• Microvilli/pathology
• Mucolipidoses
• Myosin Type V/genetics
• Myosin Type V/metabolism
• Sodium/metabolism
• Water/metabolism

• R01 DK048370 NIDDK NIH HHS
• R01 DK128190 NIDDK NIH HHS
• RC2 DK118640 NIDDK NIH HHS
• T32 GM007628 NIGMS NIH HHS

• MYO5B
• UNC45A
• chaperone
• microvillus inclusion disease
• myosin Vb
• osteo-oto-hepato-enteric syndrome

Microvillus inclusion disease (MVID) is a rare enteropathy caused by mutations in the MYO5B or STX3 gene. MVID is a disease that is difficult to manage with clinical heterogeneity. Therefore, knowledge about factors influencing MVID morbidity and mortality is urgently needed. Triggered by a recent study that reported a high percentage of preterm births in twelve cases of MVID, we have conducted a comprehensive retrospective study involving 88 cases of MVID with reported gestational ages. We found that moderate to late preterm birth occurred in more than half of all cases, and this was particularly prominent in MYO5B-associated MVID. Preterm birth in MVID counterintuitively correlated with higher birth weight percentiles, and correlated with higher stool outputs and a significantly shorter average survival time. Data from this study thus demonstrate an increased risk of preterm birth in MYO5B-associated MVID, with a clinical impact on morbidity and mortality. Adverse effects associated with preterm birth should be taken into account in the care of children diagnosed with MVID. Documentation of gestational age may contribute to a better prognostic risk assessment in MVID.

• MYO5B
• PFIC
• STX3
• congenital diarrheal disorder
• congenital microvillus atrophy
• intrahepatic cholestasis
• microvillus inclusion disease
• premature birth
• preterm birth

The FDA-approved drug ivermectin is applied for treatments of onchocerciasis and lymphatic filariasis. The anti-cancer and anti-viral activities have been demonstrated stressing possibilities for the drug repurposing and therefore new information on high dosage safety is on demand. We analyzed in vivo tissue responses for high doses of ivermectin using Corydoras fish as animal model. We made intestinal histology and hematologic assays after oral administration of ivermectin transported with polyelectrolytes formulation. Histology showed any apparent damage of intestinal tissues at 0.22–170 mg of ivermectin/kg body weight. Immunofluorescence evidenced delocalization of Myosin-Vb at enterocytes only for the higher dose. Hematology parameters showed random variations after 7 days from administration, but a later apparent recover after 14 and 21 days. The study evaluated the potential of high doses of oral administration of ivermectin formulation, which could be an alternative with benefits in high compliance therapies.

• Animal model
• Drug repurposing
• Formulation
• High dosage
• Histochemistry
• Immunofluorescence

Microvillus inclusion disease (MVID) is a rare inherited and invariably fatal enteropathy, characterized by severe intractable secretory diarrhea and nutrient malabsorption. No cure exists, and patients typically die during infancy because of treatment-related complications. The need for alternative treatment strategies is evident. Several pharmacological interventions with variable successes have been tried and reported for individual patients as part of their clinical care. Unfortunately, these interventions and their outcomes have remained hidden in case reports and have not been reviewed. Further, recent advances regarding MVID pathogenesis have shed new light on the outcomes of these pharmacological interventions and offer suggestions for future clinical research and trials. Hence, an inventory of reported pharmacological interventions in MVID, their rationales and outcomes, and a discussion of these in the light of current knowledge is opportune. Together with a discussion on MVID-specific pharmacokinetic, -dynamic, and -genetic concerns that pose unique challenges regarding pharmacological strategies, we envision that this paper will aid researchers and clinicians in their efforts to develop pharmacological interventions to combat this devastating disease.

• MYO5B
• congenital diarrheal disorder
• malabsorption
• microvillus inclusion disease
• myosin Vb

• Blindness
• Cancer
• Cardiopmyopathy
• Colitis
• Deafness
• Disease
• Glomerulosclerosis
• Infectious disease
• Microvillous inclusion disease
• Myosins
• Neurological defects

Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors.

Up to 25% of pheochromocytoma/paraganglioma (PPGL) cases develop metastatic disease with poor outcome and few treatment options. The disease mechanism is not fully understood, and to date there are no reliable markers to predict malignancy. We have recently discovered novel missense mutations in the non-conventional myosin 5 gene (MYO5B), an endosomal transport protein, which we now show enhances progression and migration in PPGLs. MYO5B mutations were preferentially found in patients with metastatic disease and SDH deficiency (germline SDHB-mutations). Abolished SDH activity result in a metabolic switch to aerobic glycolysis requiring increased glucose consumption. Since the MYO5B mutations were found to drive progression through downstream up-regulation of glucose metabolism genes, e.g. glucagon, we hypothesize that these mutations may fuel the pseudohypoxic state by altering glucose uptake in cancer cells. Our result is the first to link the myosin 5 genes to PPGL tumorigenesis. Further, it shows that the tumor progression route in PPGL is complex, with contribution from several genetic factors. An increasing number of studies show dysregulation and importance of the MYO5-proteins in cancer, but little is still known about the precise role and mechanism of mutations, hence more research in this area is needed.

• Malabsorption
• Missense Mutation
• Motor Protein
• Plasma Membrane

Congenital diarrheal disorders (CDD) comprise > 50 monogenic entities featuring chronic diarrhea of early-onset, including defects in nutrient and electrolyte absorption, enterocyte polarization, enteroendocrine cell differentiation, and epithelial integrity. Diarrhea is also a predominant symptom in many immunodeficiencies, congenital disorders of glycosylation, and in some defects of the vesicular sorting and transporting machinery. We set out to identify the etiology of an intractable diarrhea in 2 consanguineous families by whole-exome sequencing, and identified two novel AP1S1 mutations, c.269T>C (p.Leu90Pro) and c.346G>A (p.Glu116Lys). AP1S1 encodes the small subunit of the adaptor protein 1 complex (AP-1), which plays roles in clathrin coat-assembly and trafficking between trans-Golgi network, endosomes and the plasma membrane. An AP1S1 knock-out (KO) of a CaCo2 intestinal cell line was generated to characterize intestinal AP1S1 deficiency as well as identified mutations by stable expression in KO background. Morphology and prototype transporter protein distribution were comparable between parental and KO cells. We observed altered localization of tight-junction proteins ZO-1 and claudin 3, decreased transepithelial electrical resistance and an increased dextran permeability of the CaCo2-AP1S1-KO monolayer. In addition, lumen formation in 3D cultures of these cells was abnormal. Re-expression of wild-type AP1S1 in CaCo2-AP1S1-KO cells reverted these abnormalities, while expression of AP1S1 containing either missense mutation did not. Our data indicate that loss of AP1S1 function causes an intestinal epithelial barrier defect, and that AP1S1 mutations can cause a non-syndromic form of congenital diarrhea, whereas 2 reported truncating AP1S1 mutations caused MEDNIK syndrome, characterized by mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia.

Microvillus inclusion disease (MVID) is a rare congenital severe malabsorptive and secretory diarrheal disease characterized by blunted or absent microvilli with accumulation of secretory granules and inclusion bodies in enterocytes. The typical clinical presentation of the disease is severe chronic diarrhea that rapidly leads to dehydration and metabolic acidosis. Despite significant advances in our understanding of the causative factors, to date, no curative therapy for MVID and associated diarrhea exists. Prognosis mainly relies on life-long total parenteral nutrition (TPN) and eventual small bowel and/or liver transplantation. Both TPN and intestinal transplantation are challenging and present with many side effects. A breakthrough in the understanding of MVID emanated from seminal findings revealing mutations in MYO5B as a cause for MVID. During the last decade, many studies have thus utilized cell lines and animal models with knockdown of MYO5B to closely recapitulate the human disease and investigate potential therapeutic options in disease management. We will review the most recent advances made in the research pertaining to MVID. We will also highlight the tools and models developed that can be utilized for basic and applied research to increase our understanding of MVID and develop novel and effective targeted therapies.

• MVID
• diarrhea
• epithelial transport
• malabsorption
• trafficking

• Bile acids
• Cholestasis
• Genetics
• PFIC
• Pediatrics

• Rab GAP
• Rab GEF
• Rab GTPases
• Rab binding partners
• Rab effectors
• membrane trafficking

• Amino Acid Sequence
• Animals
• Conserved Sequence
• Humans
• Protein Binding
• rab GTP-Binding Proteins/chemistry
• rab GTP-Binding Proteins/metabolism

The intestinal epithelium is a highly organized tissue. The establishment of epithelial cell polarity, with distinct apical and basolateral plasma membrane domains, is pivotal for both barrier formation and for the uptake and vectorial transport of nutrients. The establishment of cell polarity requires a specialized subcellular machinery to transport and recycle proteins to their appropriate location. In order to understand and treat polarity-associated diseases, it is necessary to understand epithelial cell-specific trafficking mechanisms. In this Review, we focus on cell polarity in the adult mammalian intestine. We discuss how intestinal epithelial polarity is established and maintained, and how disturbances in the trafficking machinery can lead to a polarity-associated disorder, microvillus inclusion disease (MVID). Furthermore, we discuss the recent developments in studying MVID, including the creation of genetically manipulated cell lines, mouse models and intestinal organoids, and their uses in basic and applied research.

Summary: Microvillus inclusion disease serves as a useful model to enhance our understanding of the intestinal trafficking and polarity machinery in health and disease.

• Epithelial cells
• Intestine
• Microvillus inclusion disease
• Polarity

• Cell Biology
• Epithelial transport of ions and water
• Gastroenterology
• Molecular genetics
• Protein traffic

Rab molecular switches are key players in defining membrane identity and regulating intracellular trafficking events in eukaryotic cells. In spite of their global structural similarity, Rab-family members acquired particular features that allow them to perform specific cellular functions. The overall fold and local sequence conservations enable them to utilize a common machinery for prenylation and recycling; while individual Rab structural differences determine interactions with specific partners such as GEFs, GAPs and effector proteins. These interactions orchestrate the spatiotemporal regulation of Rab localization and their turning ON and OFF, leading to tightly controlled Rab-specific functionalities such as membrane composition modifications, recruitment of molecular motors for intracellular trafficking, or recruitment of scaffold proteins that mediate interactions with downstream partners, as well as actin cytoskeleton regulation.

In this review we summarize structural information on Rab GTPases and their complexes with protein partners in the context of partner binding specificity and functional outcomes of their interactions in the cell.

• Rab GAP
• Rab GEF
• Rab GTPases
• Rab binding partners
• Rab effectors
• membrane trafficking

• Enterocyte
• Microvillus formation
• Neonatal enteropathy
• Rab11a
• Rab8a

• Myo5b
• NHE3
• Rab Small GTPases
• Rab11a
• Rab8a
• Stx3
• congenital diarrheal disorder
• electron tomography
• hereditary enteropathy
• immunoelectron microscopy

• Enteropathy
• MVID
• MYO5B
• Microvillus inclusion disease
• STX3

Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDD^ENT) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDD^ENT. Here, we review recent progress in understanding the cellular mechanisms of CDD^ENT. We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDD^ENT and expediting the discovery of novel therapeutic strategies.

Summary: Overview of the recent progress in our understanding of congenital diarrheal disorders, and the available models to study these diseases.

• Brush border
• Cell polarity
• Congenital diarrheal disorder
• Enterocyte
• Intracellular trafficking
• Microvillus inclusion diseases

Microvillus inclusion disease (MVID) is a life-threatening enteropathy characterised by malabsorption and incapacitating fluid loss due to chronic diarrhoea. Histological analysis has revealed that enterocytes in MVID patients exhibit reduction of microvilli, presence of microvillus inclusion bodies and intestinal villus atrophy, whereas genetic linkage analysis has identified mutations in myosin Vb gene as the main cause of MVID. In order to understand the cellular basis of MVID and the associated formation of inclusion bodies, an animal model that develops ex utero and is tractable genetically as well as by microscopy would be highly useful. Here we report that the intestine of the zebrafish goosepimples (gsp)/myosin Vb (myoVb) mutant shows severe reduction in intestinal folds - structures similar to mammalian villi. The loss of folds is further correlated with changes in the shape of enterocytes. In striking similarity with MVID patients, zebrafish gsp/myoVb mutant larvae exhibit microvillus atrophy, microvillus inclusions and accumulation of secretory material in enterocytes. We propose that the zebrafish gsp/myoVb mutant is a valuable model to study the pathophysiology of MVID. Furthermore, owing to the advantages of zebrafish in screening libraries of small molecules, the gsp mutant will be an ideal tool to identify compounds having therapeutic value against MVID.

•

myosin Vb is expressed in the zebrafish intestine.

• Disease model
• Gut morphogenesis
• Intestine
• Microvillus inclusion disease
• Zebrafish

The motor protein Myo5B and t-SNARE Stx3 drive cargo-selective apical exocytosis in polarized epithelial cells in a pathway dependent on v-SNARE–like Slp4a, v-SNARE Vamp7, Sec1/Munc18-like protein Munc18-2, and the Rab11/8 cascade.

Mutations in the motor protein Myosin Vb (Myo5B) or the soluble NSF attachment protein receptor Syntaxin 3 (Stx3) disturb epithelial polarity and cause microvillus inclusion disease (MVID), a lethal hereditary enteropathy affecting neonates. To understand the molecular mechanism of Myo5B and Stx3 interplay, we used genome editing to introduce a defined Myo5B patient mutation in a human epithelial cell line. Our results demonstrate a selective role of Myo5B and Stx3 for apical cargo exocytosis in polarized epithelial cells. Apical exocytosis of NHE3, CFTR (cystic fibrosis transmembrane conductance regulator), and GLUT5 required an interaction cascade of Rab11, Myo5B, Slp4a, Munc18-2, and Vamp7 with Stx3, which cooperate in the final steps of this selective apical traffic pathway. The brush border enzymes DPPIV and sucrase-isomaltase still correctly localize at the apical plasma membrane independent of this pathway. Hence, our work demonstrates how Myo5B, Stx3, Slp4a, Vamp7, Munc18-2, and Rab8/11 cooperate during selective apical cargo trafficking and exocytosis in epithelial cells and thereby provides further insight into MVID pathophysiology.

• Enterocyte trafficking
• NHE3
• Rab11a
• Rab8a
• Syntaxin 3
• brush border

• R01 DK048370 NIDDK NIH HHS
• R56 DK070856 NIDDK NIH HHS
• T32 DK007673 NIDDK NIH HHS
• P30 DK058404 NIDDK NIH HHS
• P30 HD015052 NICHD NIH HHS
• P30 DK020593 NIDDK NIH HHS
• R01 DK070856 NIDDK NIH HHS
• P30 CA068485 NCI NIH HHS

• ATP7B
• Apical
• Cu+
• Endosome
• Hepatocyte
• Myosin
• Trafficking

• Celiac disease
• Epithelial polarity
• MVID
• Membrane traffic
• Myo5B
• Trichohepatoenteric syndrome

• epithelila polarity
• intestinal enteropathy
• microvillus inclusion disease
• mouse model
• myosin Vb

Inherited MYO5B mutations have recently been associated with microvillus inclusion disease (MVID), an autosomal recessive syndrome characterized by intractable, life-threatening, watery diarrhea appearing shortly after birth. Characterization of the molecular mechanisms underlying this disease and development of novel therapeutic approaches is hampered by the lack of animal models. In this study we describe the phenotype of a novel mouse model with targeted inactivation of Myo5b. Myo5b knockout mice show perinatal mortality, diarrhea and the characteristic mislocalization of apical and basolateral plasma membrane markers in enterocytes. Moreover, in transmission electron preparations, we observed microvillus atrophy and the presence of microvillus inclusion bodies. Importantly, Myo5b knockout embryos at day 20 of gestation already display all these structural defects, indicating that they are tissue autonomous rather than secondary to environmental cues, such as the long-term absence of nutrients in the intestine. Myo5b knockout mice closely resemble the phenotype of MVID patients and constitute a useful model to further investigate the underlying molecular mechanism of this disease and to preclinically assess the efficacy of novel therapeutic approaches.

Microscopic enteritis (ME) is an inflammatory condition of the small bowel that leads to gastrointestinal symptoms, nutrient and micronutrient deficiency. It is characterised by microscopic or sub-microscopic abnormalities such as microvillus changes and enterocytic alterations in the absence of definite macroscopic changes using standard modern endoscopy. This work recognises a need to characterize disorders with microscopic and submicroscopic features, currently regarded as functional or non-specific entities, to obtain further understanding of their clinical relevance. The consensus working party reviewed statements about the aetiology, diagnosis and symptoms associated with ME and proposes an algorithm for its investigation and treatment. Following the 5^th International Course in Digestive Pathology in Bucharest in November 2012, an international group of 21 interested pathologists and gastroenterologists formed a working party with a view to formulating a consensus statement on ME. A five-step agreement scale (from strong agreement to strong disagreement) was used to score 21 statements, independently. There was strong agreement on all statements about ME histology (95%-100%). Statements concerning diagnosis achieved 85% to 100% agreement. A statement on the management of ME elicited agreement from the lowest rate (60%) up to 100%. The remaining two categories showed general agreement between experts on clinical presentation (75%-95%) and pathogenesis (80%-90%) of ME. There was strong agreement on the histological definition of ME. Weaker agreement on management indicates a need for further investigations, better definitions and clinical trials to produce quality guidelines for management. This ME consensus is a step toward greater recognition of a significant entity affecting symptomatic patients previously labelled as non-specific or functional enteropathy.

• Microscopic enteritis
• Enteropathy
• Gluten
• Malabsorption
• Non-celiac gluten
• Bucharest consensus

• Algorithms
• Comorbidity
• Consensus
• Critical Pathways
• Enteritis/classification
• Enteritis/diagnosis
• Enteritis/epidemiology
• Enteritis/physiopathology
• Enteritis/therapy
• Humans
• Intestinal Absorption
• Intestine, Small/pathology
• Intestine, Small/physiopathology
• Predictive Value of Tests
• Prognosis
• Risk Factors

• Enterocyte
• Intestinal polarity
• Microvilli
• Rab11
• Rab8
• Syntaxin 3

• apical recycling endosome
• atypical protein kinase C
• endothelial polarity
• phosphoinositide-dependent protein kinase 1
• small Ras-like guanosine 3′,5′-monophosphate

• PCD
• ciliogenesis
• primary ciliary dyskinesia

• Epithelial Polarity
• Syntaxin 3
• Variant Microvillus Inclusion Disease