title: 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.forename: Amélie E
authors.initials: AE
authors.lastname: Bigorgne
authors.forename: Henner F
authors.initials: HF
authors.lastname: Farin
authors.forename: Roxane
authors.initials: R
authors.lastname: Lemoine
authors.forename: Nizar
authors.initials: N
authors.lastname: Mahlaoui
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambert
authors.forename: Marine
authors.initials: M
authors.lastname: Gil
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schulz
authors.forename: Pierre
authors.initials: P
authors.lastname: Philippet
authors.forename: Patrick
authors.initials: P
authors.lastname: Schlesser
authors.forename: Tore G
authors.initials: TG
authors.lastname: Abrahamsen
authors.forename: Knut
authors.initials: K
authors.lastname: Oymar
authors.forename: E Graham
authors.initials: EG
authors.lastname: Davies
authors.forename: Christian Lycke
authors.initials: CL
authors.lastname: Ellingsen
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Leteurtre
authors.forename: Brigitte
authors.initials: B
authors.lastname: Moreau-Massart
authors.forename: Dominique
authors.initials: D
authors.lastname: Berrebi
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Patrick
authors.initials: P
authors.lastname: Nischke
authors.forename: Nicole
authors.initials: N
authors.lastname: Brousse
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D001483:Base Sequence; D016764:Cell Polarity; D002478:Cells, Cultured; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004847:Epithelial Cells / Q000502:physiology; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D007409:Intestinal Atresia / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D007413:Intestinal Mucosa / Q000473:pathology*; D008198:Lymph Nodes / Q000473:pathology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D010375:Pedigree; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D013950:Thymus Gland / Q000002:abnormalities / Q000473:pathology; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D011506:Proteins; C583818:TTC7A protein, human; D054460:rho-Associated Kinases