TTC7A mutations disrupt intestinal epithelial apicobasal polarity

J Clin Invest. 2014 Jan;124(1):328-37. doi: 10.1172/JCI71471.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Polarity
  • Cells, Cultured
  • Child
  • Consanguinity
  • DNA Mutational Analysis
  • Epithelial Cells / physiology
  • Exome
  • Female
  • Genetic Association Studies
  • Genetic Linkage
  • Humans
  • Infant
  • Intestinal Atresia / genetics*
  • Intestinal Atresia / immunology
  • Intestinal Atresia / mortality
  • Intestinal Atresia / pathology
  • Intestinal Mucosa / pathology*
  • Lymph Nodes / pathology
  • Lymphopenia / genetics
  • Lymphopenia / immunology
  • Lymphopenia / pathology
  • Male
  • Pedigree
  • Proteins / genetics*
  • Proteins / metabolism
  • Severe Combined Immunodeficiency / genetics*
  • Severe Combined Immunodeficiency / immunology
  • Severe Combined Immunodeficiency / mortality
  • Severe Combined Immunodeficiency / pathology
  • Thymus Gland / abnormalities
  • Thymus Gland / pathology
  • rho-Associated Kinases / metabolism


  • Proteins
  • TTC7A protein, human
  • rho-Associated Kinases

Supplementary concepts

  • Intestinal Atresia, Multiple