Article

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.

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Available from: Nicolas André, Aug 30, 2015
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    • "In 2007, we proposed to group the two syndromes under the same entity [1]. This suggestion was proven relevant with the imputation of TTC37[2,3] as causative of 2/3 of SD/THE cases, without clear clinical delineation. More recently, the identification of SKIV2L mutations as causing the missing third of SD/THE permitted us to confirm the unity of the syndrome [4]. "
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    ABSTRACT: Syndromic diarrhea/Tricho-hepato-enteric syndrome (SD/THE) is a rare and severe bowel disorder caused by mutation in SKIV2L or in TTC37, 2 genes encoding subunits of the putative human SKI complex. The estimated prevalence is 1/1,000,000 births and the transmission is autosomal recessive. The classical form is characterized by 5 clinical signs: intractable diarrhea of infancy beginning in the first month of life, usually leading to failure to thrive and requiring parenteral nutrition; facial dysmorphism characterised by prominent forehead and cheeks, broad nasal root and hypertelorism; hair abnormalities described as woolly and easily removable; immune disorders resulting from defective antibody production; intrauterine growth restriction. The aetiology is a defect in TTC37, a TPR containing protein, or in the RNA helicase SKIV2L, both constituting the putative human ski complex. The ski complex is a heterotetrameric cofactor of the cytoplasmic RNA exosome which ensures aberrants mRNAs decay. The diagnosis SD/THE is initially based on clinical findings and confirmed by direct sequencing of TTC37 and SKIV2L. Differential diagnosis with the other causes of intractable diarrhea is easily performed by pathologic investigations. During their clinical course, most of the children require parenteral nutrition and often immunoglobulin supplementation. With time, some of them can be weaned off parenteral nutrition and immunoglobulin supplementation. The prognosis depends on the management and is largely related to the occurrence of parenteral nutrition complications or infections. Even with optimal management, most of the children seem to experience failure to thrive and final short stature. Mild mental retardation is observed in half of the cases.
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    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.
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    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.
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