title: Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy).
abstract: OBJECTIVE
  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 alpha-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.
authors.affiliation: Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham College of Medical and Dental School, Institute of Biomedical Research, Edgbaston, Birmingham, UK. janehartley@doctors.org.uk
authors.forename: Jane Louise
authors.initials: JL
authors.lastname: Hartley
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Zachos
authors.forename: Ban
authors.initials: B
authors.lastname: Dawood
authors.forename: Mark
authors.initials: M
authors.lastname: Donowitz
authors.forename: Julia
authors.initials: J
authors.lastname: Forman
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Pollitt
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.forename: Louise
authors.initials: L
authors.lastname: Tee
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.forename: Walter H A
authors.initials: WH
authors.lastname: Kahr
authors.forename: Alex S
authors.initials: AS
authors.lastname: Knisely
authors.forename: Steve
authors.initials: S
authors.lastname: Watson
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Ian W
authors.initials: IW
authors.lastname: Booth
authors.forename: Sue
authors.initials: S
authors.lastname: Protheroe
authors.forename: Stephen
authors.initials: S
authors.lastname: Murphy
authors.forename: Esther
authors.initials: E
authors.lastname: de Vries
authors.forename: Deirdre A
authors.initials: DA
authors.lastname: Kelly
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000293:Adolescent; D001792:Blood Platelets / Q000648:ultrastructure; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D019295:Computational Biology; D003968:Diarrhea, Infantile / Q000097:blood / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000032:analysis; D013577:Syndrome
chemical_list: D002352:Carrier Proteins; C081517:SLC9A2 protein, human; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; C550452:TTC37 protein, human