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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

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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 1

Immunological characteristics of MIA-CID patients.

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Immunological characteristics of MIA-CID patients.
(A) Circulating blood...
(A) Circulating blood cell counts. Shown are lymphocyte, monocyte, and neutrophil counts as well as total CD3+, CD4+, and CD8+ T cell counts. (B) Thymus pathology. H&E staining (top) revealed poor corticomedullary demarcation and a paucity of lymphocytes and Hassall’s bodies in A4 versus a control subject. Also shown is immunohistochemical staining of CD3, CD8, and CD4 as well as CK5 and CK8 staining for medullary (m) and cortical (c) thymic epithelial cells, respectively. (C) Mediastinal lymph node. H&E staining and immunohistochemical staining for CD20, CD3, and CD68 in a control subject and in E3 after autopsy. Original magnification, ×50 (B), ×400 (B, enlarged H&E views), ×200 (C, H&E), ×100 (C, immunostaining).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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