TTC37 – Trichohepatoenteric Syndrome

Trichohepatoenteric syndrome (THE-S) is a rare autosomal recessive multisystem disorder characterized by early-onset intractable diarrhea, facial dysmorphism, immunodeficiency, woolly hair, and variable liver disease (PMID:20176027). The disease is caused by biallelic pathogenic variants in TTC37, encoding the tetratricopeptide repeat protein Thespin, a component of the cytoplasmic SKI mRNA decay complex.

Genetic studies have identified TTC37 mutations in over 100 affected individuals from at least 11 unrelated families, including homozygous and compound heterozygous missense, nonsense, splice-site, and frameshift variants (PMID:20176027; PMID:34414925). Segregation analysis in consanguineous pedigrees and multiplex families has confirmed autosomal recessive inheritance and co-segregation of TTC37 variants with disease in at least 19 affected relatives.

The variant spectrum in TTC37 includes over 30 distinct alleles: missense substitutions, such as c.4507C>T (p.Arg1503Cys) (PMID:28292286); nonsense variants (e.g., c.1708C>T (p.Arg570Ter)); canonical splice-site changes; and small insertions/deletions causing frameshifts and premature termination. No mutation hotspots are evident, and a founder variant c.2808G>A (p.Trp936Ter) has been reported in South Asian populations (PMID:23326254).

Functional assays support TTC37 haploinsufficiency: immunohistochemistry of patient enterocytes shows mislocalization and reduced expression of brush-border ion transporters, and yeast complementation demonstrates that Ski3p (yeast ortholog) forms a trimeric complex essential for 3′–5′ mRNA decay (PMID:20176027; PMID:10744028). Loss of Thespin function disrupts mRNA surveillance pathways and likely underlies epithelial barrier defects and immune dysregulation.

No studies to date have refuted the TTC37–THE-S association. All reported variants are consistent with recessive inheritance and pathogenicity, and functional findings across patient-derived tissues and model systems are concordant with the clinical phenotype.

In summary, TTC37 has a definitive association with trichohepatoenteric syndrome, supported by extensive genetic and experimental data. Clinical testing for TTC37 variants enables precise diagnosis, informs family counseling, and guides nutritional and immunological management. Key Take-home: Biallelic TTC37 mutations cause THE-S via impaired mRNA decay, and molecular diagnosis is critical for patient care and genetic counselling.

References

• Gastroenterology • 2010 • Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy). PMID:20176027
• BMC Medical Genetics • 2017 • Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa. PMID:28292286
• RNA • 2000 • The yeast antiviral proteins Ski2p, Ski3p, and Ski8p exist as a complex in vivo. PMID:10744028
• Saudi Journal of Gastroenterology • 2022 • Tricho-hepato-enteric syndrome: Retrospective multicenter experience in Saudi Arabia. PMID:34414925
• Molecular Syndromology • 2012 • Trichohepatoenteric syndrome: founder mutation in asian indians. PMID:23326254

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