TY - JOUR
T1 - TTC7A mutations disrupt intestinal epithelial apicobasal polarity
AU - Bigorgne, Amélie E.
AU - Farin, Henner F.
AU - Lemoine, Roxane
AU - Mahlaoui, Nizar
AU - Lambert, Nathalie
AU - Gil, Marine
AU - Schulz, Ansgar
AU - Philippet, Pierre
AU - Schlesser, Patrick
AU - Abrahamsen, Tore G.
AU - Oymar, Knut
AU - Graham Davies, E.
AU - Ellingsen, Christian Lycke
AU - Leteurtre, Emmanuelle
AU - Moreau-Massart, Brigitte
AU - Berrebi, Dominique
AU - Bole-Feysot, Christine
AU - Nischke, Patrick
AU - Brousse, Nicole
AU - Fischer, Alain
AU - Clevers, Hans
AU - De Saint Basile, Geneviève
PY - 2014/1/2
Y1 - 2014/1/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84892928479&partnerID=8YFLogxK
U2 - 10.1172/JCI71471
DO - 10.1172/JCI71471
M3 - Article
AN - SCOPUS:84892928479
SN - 0021-9738
VL - 124
SP - 328
EP - 337
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -