Novel mutations in TTC37 associated with tricho-hepato-enteric syndrome

Service de Pédiatrie Multidisciplinaire, Hôpital d'enfants de la Timone, Marseille, France.
Human Mutation (Impact Factor: 5.05). 03/2011; 32(3):277-81. DOI: 10.1002/humu.21420
Source: PubMed

ABSTRACT The Tricho-Hepato-Enteric (THE) syndrome is an autosomal recessive condition marked by early and intractable diarrhea, hair abnormalities, and immune defects. Mutations in TTC37, which encodes the putative protein Thespin, have recently been associated with THE syndrome. In this article, we extend the pattern of TTC37 mutations by the description of 11 novel mutations in 9 patients with a typical THE syndrome. The mutations were spread along the gene sequence, none of themrecurrent. Different types of mutation were observed: frameshift mutations, splice-site altering mutations, or missense mutations, most of them leading to the creation of a premature stop codon. Concurrently, we investigated the pattern of TTC37 expression in a panel of normal human tissues and showed that this gene is widely expressed, with high levels in vascular tissues, lymph node, pituitary, lung, and intestine. In contrast, TTC37 is not expressed in the liver, an organ that is not consistently affected in THE syndrome. Last, we suggested a model for the putative structure of the unknown Thespin protein.

Download full-text


Available from: Nicolas André, Jun 30, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease.
    The American Journal of Human Genetics 03/2012; 90(4):689-92. DOI:10.1016/j.ajhg.2012.02.009 · 10.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Trichohepatoenteric syndrome (THES) is characterized by chronic diarrhea, dysmorphic facies and hair abnormalities. Hepatic involvement varies from no abnormality to cirrhosis and hemochromatosis. Recently, mutations in the tetratricopeptide repeat domain 37 (TTC37) gene were identified to cause THES. The c.2808G>A variation was suggested as a possible founder mutation among the South Asians. We further report 2 unrelated cases of Asian-Indian ethnicity (Gujrati) with THES, wherein targeted mutation analysis revealed the same mutation in homozygous form in both cases. These findings, as well as haplotype analysis, corroborate the founder mutation hypothesis amongst Asian Indo-Pakistani ethnic groups. A restriction enzyme-based method is also described to identify this founder mutation. One of our probands had multiple hepatic hemangiomas, a feature not previously observed in this syndrome.
    Molecular syndromology 08/2012; 3(2):89-93. DOI:10.1159/000339896
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nonstop decay is the mechanism of identifying and disposing aberrant transcripts that lack in-frame stop codons. It is hypothesized that these transcripts are identified during translation when the ribosome arrives at the 3' end of the mRNA and stalls. Presumably, the ribosome stalling recruits additional cofactors, Ski7 and the exosome complex. The exosome degrades the transcript using either one of its ribonucleolytic activities, and the ribosome and the peptide are both released. Additional precautionary measures by the nonstop decay pathway may include translational repression of the nonstop transcript after translation, and proteolysis of the released peptide by the proteasome. This surveillance mechanism protects the cells from potentially harmful truncated proteins, but it may also be involved in mediating critical cellular functions of transcripts that are prone to stop codon read-through. Important advances have been made in the past decade as we learn that nonstop decay may have implications in human disease.
    WIREs RNA 09/2012; 3(5):649-60. DOI:10.1002/wrna.1124 · 6.15 Impact Factor