TTC7A – Multiple Intestinal Atresia

Multiple intestinal atresia (MIA; MONDO:0009465) is a severe congenital gastrointestinal obstruction often accompanied by combined immunodeficiency. Biallelic mutations in TTC7A (HGNC:19750; Gene Symbol) underlie autosomal recessive MIA, manifesting with multiple small and large bowel atresias, lymphopenia, villous atrophy, polyhydramnios, and umbilical hernia.

Genetic evidence includes case reports and series describing compound heterozygous or homozygous TTC7A mutations in over 30 unrelated probands: a newborn with c.2482C>T (p.Gln828Ter) and c.2368_2369insCGCC (p.Ser790fs) (PMID:24931897), five infants with compound loss-of-function alleles including c.2482C>T (p.Gln828Ter) and c.1576C>T (p.Gln526Ter) (PMID:24417819), and a consanguineous pedigree of 13 affected siblings with missense and splice variants (PMID:25174867). Variant classes span nonsense, frameshift, splice-site, and missense changes; for example, c.1498C>T (p.Gln500Ter) represents a recurrent stop gain in unrelated families (PMID:24292712).

Segregation analysis reveals autosomal recessive inheritance with co-segregation of biallelic TTC7A variants in multiple affected relatives (n=13) (PMID:25174867). Carrier frequency data remain limited but the recurrence of founder alleles in consanguineous populations has been noted. No reported cases with heterozygous TTC7A variants alone exhibit the MIA–immunodeficiency phenotype.

Functional studies in patient-derived intestinal organoids demonstrate inversion of epithelial apicobasal polarity due to increased Rho kinase activity, reversible by Rho kinase inhibitors (PMID:24292712). Biochemical assays confirm that TTC7A interacts with EFR3B to recruit phosphatidylinositol 4-kinase, and that loss-of-function mutations reduce complex formation, impairing enterocyte adhesion, increasing apoptosis, and disrupting PI4P production (PMID:24417819). In immune cells, TTC7A deficiency alters RhoA signaling, leading to lymphocyte migration and proliferation defects that contribute to combined immunodeficiency (PMID:25174867).

The mechanism of pathogenicity is loss of TTC7A function resulting in disturbed epithelial polarity and immune cell homeostasis. Animal models (fsn and hea mice) with Ttc7 intronic insertions or deletions recapitulate skin, anemia, and immune phenotypes, reinforcing causality and highlighting TTC7A’s role as a scaffold in PI4K signaling (Experimental Biology and Medicine • 2005 [PMID:16179734]; Genomics • 2005 [PMID:15718100]).

Collectively, TTC7A meets criteria for a Definitive gene–disease association based on replication in multiple cohorts, segregation in large families, and concordant functional data. Genetic testing for TTC7A variants is recommended in infants with MIA and immunodeficiency, guiding early diagnosis, family counseling, and potential targeted therapies such as Rho kinase inhibitors.

References

• The Journal of clinical investigation • 2014 • TTC7A mutations disrupt intestinal epithelial apicobasal polarity. PMID:24292712
• Gastroenterology • 2014 • Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. PMID:24417819
• The Journal of allergy and clinical immunology • 2014 • Immune deficiency-related enteropathy-lymphocytopenia-alopecia syndrome results from tetratricopeptide repeat domain 7A deficiency. PMID:25174867
• Journal of clinical immunology • 2014 • Tetratricopeptide repeat domain 7A (TTC7A) mutation in a newborn with multiple intestinal atresia and combined immunodeficiency. PMID:24931897
• Experimental biology and medicine (Maywood, N.J.) • 2005 • The Tetratricopeptide repeat domain 7 gene is mutated in flaky skin mice: a model for psoriasis, autoimmunity, and anemia. PMID:16179734
• Genomics • 2005 • Positional cloning of the Ttc7 gene required for normal iron homeostasis and mutated in hea and fsn anemia mice. PMID:15718100

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