Dataset Information

Novel IRF6 mutations in Chinese Han families with Van der Woude syndrome.

ABSTRACT: BACKGROUND:Interferon Regulatory Factor 6 (IRF6) gene encodes a member of the IRF family of transcription factors. Mutations in IRF6 cause Van der Woude Syndrome (VWS), which is the most common malformation of syndromic orofacial clefts in humans. METHODS:Here, we performed sequencing studies of six families with VWS in the Chinese Han population. The entire IRF6-coding region and the exon-intron boundaries including exons 3-8 and part of exon 9 were screened among all the collected family members by Sanger sequencing. RESULTS:We found a novel splice site variant c.175-6T>A, two novel missense variants (p.Lys66Arg and p.Pro107Thr), in addition with a previously reported missense variant (p.Leu87Phe), which were all located in and nearby exon 4 of IRF6. Meanwhile, a novel frameshift variant p.G257Vfs*46 in exon 7 of IRF6 was also detected. All the mutations presented to be co-segregated in each family. CONCLUSION:Our study has advanced the understanding of the genetic architecture of VWS and provides the basis for genetic counseling, antenatal diagnosis, and gene therapy of high risk groups.

SUBMITTER: Yu Y

PROVIDER: S-EPMC7216816 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Novel IRF6 mutations in Chinese Han families with Van der Woude syndrome.

Yu Yanqin Y Wan Yatao Y Qin Chuanqi C Yue Haitang H Bian Zhuan Z He Miao M

Molecular genetics & genomic medicine 20200228 5

<h4>Background</h4>Interferon Regulatory Factor 6 (IRF6) gene encodes a member of the IRF family of transcription factors. Mutations in IRF6 cause Van der Woude Syndrome (VWS), which is the most common malformation of syndromic orofacial clefts in humans.<h4>Methods</h4>Here, we performed sequencing studies of six families with VWS in the Chinese Han population. The entire IRF6-coding region and the exon-intron boundaries including exons 3-8 and part of exon 9 were screened among all the collect ...[more]

PMID: 32108996

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Project description:BackgroundLoss-of-function mutations in interferon regulatory factor-6 (IRF6) are responsible for about 70% of cases of Van Der Woude Syndrome (VWS), an autosomal dominant developmental disorder characterized by pits and/or sinuses of the lower lip and cleft lip, cleft palate, or both.MethodsWe collected a Chinese Han VWS pedigree, performed sequencing and screening for the causal gene mutant. Initially, species conservation analysis and homology protein modeling were used to predict the potential pathogenicity of mutations. To test whether a VWS family-derived mutant variant of IRF6 retained function, we carried out rescue assays in irf6 maternal-null mutant zebrafish embryos. To assess protein stability, we overexpressed reference and family-variants of IRF6 in vitro.ResultsWe focused on a VWS family that includes a son with bilateral lip pits, uvula fissa and his father with bilateral cleft lip and palate. After sequencing and screening, a frameshift mutation of IRF6 was identified as the potential causal variant (NM.006147.3, c.1088-1091delTCTA; p.Ile363ArgfsTer33). The residues in this position are strongly conserved among species and homology modeling suggests the variant alters the protein structure. In irf6 maternal-null mutant zebrafish embryos the periderm differentiates abnormally and the embryos rupture and die during gastrulation. Injection of mRNA encoding the reference variant of human IRF6, but not of the frame-shift variant, rescued such embryos through gastrulation. Upon overexpression in HEK293FT cells, the IRF6 frame-shift mutant was relatively unstable and was preferentially targeted to the proteasome in comparison to the reference variant.ConclusionIn this VWS pedigree, a novel frameshift of IRF6 was identified as the likely causative gene variant. It is a lost function mutation which could not rescue abnormal periderm phenotype in irf6 maternal-null zebrafish and which causes the protein be unstable through proteasome-dependent degradation.

Dataset Information

Novel IRF6 mutations in Chinese Han families with Van der Woude syndrome.

Publications

Novel IRF6 mutations in Chinese Han families with Van der Woude syndrome.

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