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Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome.

ABSTRACT: BACKGROUND:Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease. AIM:To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis. METHODS:Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function. RESULTS:We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein's packing, or changes at the protein's interface. CONCLUSIONS:THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.

SUBMITTER: Vardi I

PROVIDER: S-EPMC6167312 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome.

Vardi Iddo I Barel Ortal O Sperber Michal M Schvimer Michael M Nunberg Moran M Field Michael M Ouahed Jodie J Marek-Yagel Dina D Werner Lael L Haberman Yael Y Lahad Avishay A Anikster Yair Y Rechavi Gideon G Barshack Iris I McElwee Joshua J JJ Maranville Joseph J Somech Raz R Snapper Scott B SB Weiss Batia B Shouval Dror S DS

Digestive diseases and sciences 20180226 5

<h4>Background</h4>Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease.<h4>Aim</h4>To report on a patient with THE syndrome and present the genetic analysis that ...[more]

PMID: 29484573

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Project description:BackgroundToxoplasma gondii is a worldwide spread pathogen which can infect all tissues of its host. The transcriptomic responses of infected brain and spleen have been reported. However, our knowledge of the global transcriptomic change in infected liver is limited. Additionally, T. gondii infection represents a highly dynamic process involving complex biological responses of the host at many levels. Herein, we describe such processes at a global level by discovering gene expression changes in mouse livers after acute infection with T. gondii ToxoDB#9 strain.ResultsGlobal transcriptomic analysis identified 2,758 differentially expressed transcripts in infected liver, of which 1,356 were significantly downregulated and 1,402 upregulated. GO and KEGG database analyses showed that host immune responses were upregulated, while the metabolic-related processes/pathways were downregulated, especially xenobiotic metabolism, fatty acid metabolism, energy metabolism, and bile biosynthesis and secretion. The metabolism of more than 800 chemical compounds including anti-Toxoplasma prescribed medicines were predicted to be modulated during acute T. gondii infection due to the downregulation of enzymes involved in xenobiotic metabolism.ConclusionsTo the best of our knowledge, this is the first global transcriptomic analysis of mouse liver infected by T. gondii. The present data indicate that during the early stage of liver infection, T. gondii can induce changes in liver xenobiotic metabolism, upregulating inflammatory response and downregulating hepatocellular PPAR signaling pathway, altering host bile biosynthesis and secretion pathway; these changes could enhance host intestinal dysbacteriosis and thus contribute to the pathological changes of both liver and intestine of infected mice. These findings describe the biological changes in infected liver, providing a potential mechanistic pathway that links hepatic and intestinal pathologies to T. gondii infection.

Dataset Information

Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome.

Publications

Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome.

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