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 6

ROCK targets responsible for cytoskeleton assembly.

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ROCK targets responsible for cytoskeleton assembly. Modulation of cytosk...
Modulation of cytoskeleton assembly is required for the coordination of cell adhesion, polarization and migration. The active form of RhoA (RhoA-GTP) activates ROCK and interacts with the integrin intracellular signaling pathway. RhoA also modulates cytoskeleton reorganization via focal adhesion kinase (FAK) activation and front-rear polarity via phosphorylation of phosphatase and tensin homolog (PTEN). Phosphorylation of ROCK’s downstream effector MLC is required for the assembly of actomyosin complexes. ROCK downregulates the MLC phosphatase (MLCPase), resulting in an increase in phosphorylated MLC, cell contraction, actin organization, stress fiber formation, and focal adhesions, which confer contractility and migration properties to the cell. Phosphorylation of ROCK’s downstream effector ERM has a role in microvilli formation. Phosphorylated LIM domain kinase (LIM-K) phosphorylates and thus deactivates the actin-depolymerizing protein cofilin. Y-27632 blocks Rho-induced actomyosin activation. These data support a role for TTC7A in the downregulation of ROCK activity. Activation and inactivation are shown as arrowheads and blunted lines, respectively. MLCK, myosin light chain kinase; NHE1, Na+/H+ exchange protein.