Document Detail

TTC7A mutations disrupt intestinal epithelial apicobasal polarity.
MedLine Citation:
PMID:  24292712     Owner:  NLM     Status:  MEDLINE    
Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain–7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.
Amélie E Bigorgne; Henner F Farin; Roxane Lemoine; Nizar Mahlaoui; Nathalie Lambert; Marine Gil; Ansgar Schulz; Pierre Philippet; Patrick Schlesser; Tore G Abrahamsen; Knut Oymar; E Graham Davies; Christian Lycke Ellingsen; Emmanuelle Leteurtre; Brigitte Moreau-Massart; Dominique Berrebi; Christine Bole-Feysot; Patrick Nischke; Nicole Brousse; Alain Fischer; Hans Clevers; Geneviève de Saint Basile
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  124     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2014 Jan 
Date Detail:
Created Date:  2014-02-12     Completed Date:  2014-03-03     Revised Date:  2014-05-15    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  328-37     Citation Subset:  AIM; IM    
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MeSH Terms
Base Sequence
Cell Polarity
Cells, Cultured
DNA Mutational Analysis
Epithelial Cells / physiology
Genetic Association Studies
Genetic Linkage
Intestinal Atresia / genetics*,  immunology,  mortality,  pathology
Intestinal Mucosa / pathology*
Lymph Nodes / pathology
Lymphopenia / genetics,  immunology,  pathology
Proteins / genetics*,  metabolism
Severe Combined Immunodeficiency / genetics*,  immunology,  mortality,  pathology
Thymus Gland / abnormalities,  pathology
rho-Associated Kinases / metabolism
Reg. No./Substance:
0/Proteins; 0/TTC7A protein, human; EC Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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