Mutations in TTC37 Cause Trichohepatoenteric Syndrome (Phenotypic Diarrhea of Infancy)

Jane Louise Hartley, Nicholas C. Zachos, Ban Dawood, Mark Donowitz, Julia Forman, Rodney J. Pollitt, Neil V. Morgan, Louise Tee, Paul Gissen, Walter H.A. Kahr, Alex S. Knisely, Steve Watson, David Chitayat, Ian W. Booth, Sue Protheroe, Stephen Murphy, Esther de Vries, Deirdre A. Kelly, Eamonn R. Maher

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Background & Aims: Trichohepatoenteric syndrome (THES) is an autosomal-recessive disorder characterized by life-threatening diarrhea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation, and cardiac defects. We attempted to characterize the phenotype and elucidate the molecular basis of THES. Methods: Twelve patients with classic THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250,000 single nucleotide polymorphism arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analyzed. The effect of mutations on protein production and/or localization in hepatocytes and intestinal epithelial cells from affected patients was characterized by immunohistochemistry. Results: Previously unrecognized platelet abnormalities (reduced platelet α-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system, and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3-5q21.2. Sequencing of candidate genes showed mutations in TTC37, which encodes the uncharacterized tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (sodium hydrogen exchanger 2, sodium hydrogen exchanger 3, aquaporin 7, sodium iodide symporter, and hydrogen potassium adenosine triphosphatase [ATPase]) showed reduced expression or mislocalization in all THES patients with different profiles for each. In contrast the basolateral localization of Na/K ATPase was not altered. Conclusions: THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect, which may be owing to abnormal stability and/or intracellular localization of TTC37 target proteins.

Original languageEnglish (US)
Pages (from-to)2388-2398.e2
Issue number7
StatePublished - Jun 2010
Externally publishedYes


  • Ion Transporter Proteins
  • Phenotypic Diarrhea of Infancy
  • Platelet Alpha Granules
  • Thespin

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


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