TTC7A mutations disrupt intestinal epithelial apicobasal polarity
Amélie E. Bigorgne, … , Hans Clevers, Geneviève de Saint Basile
Amélie E. Bigorgne, … , Hans Clevers, Geneviève de Saint Basile
Published December 2, 2013
Citation Information: J Clin Invest. 2014;124(1):328-337. https://doi.org/10.1172/JCI71471.
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Research Article Gastroenterology

TTC7A mutations disrupt intestinal epithelial apicobasal polarity

Abstract

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.

Authors

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

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Figure 3

Immunohistologic studies of the digestive tract of MIA-CID patients.

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Immunohistologic studies of the digestive tract of MIA-CID patients. (A)...
(A) Pathology studies of the stomach, intestine, and colon. H&E staining of the stomach (antrum) in a control subject (12 years old) and A9 (6 months old). Asterisks denote pseudostratified epithelium; arrow denotes apoptosis in glands. Compared with the proximal small intestine in a control subject (7 days old), that of E3 (2 days old) showed cysts and protrusions of multilayered epithelial cells as well as infiltration with eosinophils. Colon was stained with H&E in a control subject (12 years old) and A9 (6 months old). (B) Immunochemical staining was performed to detect markers for epithelial differentiation as well as AP — as a marker for intestinal epithelium function — in the proximal small intestine in a control subject (1 day old) and patient (2 days old). Staining showed lamina propria infiltration by T cells (CD3) and macrophages (CD68) and Ki67-positive, proliferating epithelial cells as well as expression of CK20, villin, and AP. Original magnification, ×200 (A, stomach and colon, and B), ×50 (A, small intestine), ×400 (A, small intestine, enlarged view).