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A novel homozygous variant of GPR98 causes usher syndrome type IIC in a consanguineous Chinese family by next generation sequencing.

ABSTRACT: BACKGROUND:Usher syndrome (USH) is a common heterogeneous retinopathy and a hearing loss (HL) syndrome. However, the gene causing Usher syndrome type IIC (USH2C) in a consanguineous Chinese pedigree is unknown. METHODS:We performed targeted next-generation sequencing analysis and Sanger sequencing to explore the GPR98 mutations in a USH2C pedigree that included a 32-year-old male patient from a consanguineous marriage family. Western blot verified the nonsense mutation. RESULTS:To identify disease-causing gene variants in a consanguineous Chinese pedigree with USH2C, DNA from proband was analyzed using targeted next generation sequencing (NGS). The patient was clinically documented as a possible USH2 by a comprehensive auditory and ophthalmology evaluation. We succeeded in identifying the deleterious, novel, and homologous variant, c.6912dupG (p.Leu2305Valfs*4), in the GPR98 gene (NM_032119.3) that contributes to the progression of USH2C. Variant detected by targeted NGS was then confirmed and co-segregation was conducted by direct Sanger sequencing. Western blot verified losing almost two-thirds of its amino acid residues, including partial Calx-beta, whole EPTP and 7TM-GPCRs at the C-terminus of GPR98. Furthermore, our results highlighted that this p.Leu2305Valfs*4 variant is most likely pathogenic due to a large deletion at the seven-transmembrane G protein-coupled receptors (7TM-GPCRs) domain in GPR98 protein, leading to significantly decreased functionality and complex stability. CONCLUSIONS:These findings characterized the novel disease causativeness variant in GPR98 and broaden mutation spectrums, which could predict the pathogenic progression of patient with USH2C, guide diagnosis and treatment of this disease; and provide genetic counseling and family planning for consanguineous marriage pedigree in developing countries, including China.

SUBMITTER: Wei C

PROVIDER: S-EPMC5996530 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A novel homozygous variant of GPR98 causes usher syndrome type IIC in a consanguineous Chinese family by next generation sequencing.

Wei Chunli C Yang Lisha L Cheng Jingliang J Imani Saber S Fu Shangyi S Lv Hongbin H Li Yumei Y Chen Rui R Leung Elaine Lai-Han EL Fu Junjiang J

BMC medical genetics 20180611 1

<h4>Background</h4>Usher syndrome (USH) is a common heterogeneous retinopathy and a hearing loss (HL) syndrome. However, the gene causing Usher syndrome type IIC (USH2C) in a consanguineous Chinese pedigree is unknown.<h4>Methods</h4>We performed targeted next-generation sequencing analysis and Sanger sequencing to explore the GPR98 mutations in a USH2C pedigree that included a 32-year-old male patient from a consanguineous marriage family. Western blot verified the nonsense mutation.<h4>Results ...[more]

PMID: 29890953

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Project description:Usher syndrome is an autosomal recessive disorder that causes hearing loss, Retinitis Pigmentosa (RP) and vestibular dysfunction. It is clinically and genetically heterogeneous disorder which is clinically divided into three types i.e. type I, type II and type III. To date, there are about twelve loci and ten identified genes which are associated with Usher syndrome. A mutation in any of these genes e.g. CDH23, CLRN1, GPR98, MYO7A, PCDH15, USH1C, USH1G, USH2A and DFNB31 can result in Usher syndrome or non-syndromic deafness. These genes provide instructions for making proteins that play important roles in normal hearing, balance and vision. Studies have shown that protein structures of only seven genes have been determined experimentally and there are still three genes whose structures are unavailable. These genes are Clarin-1, GPR98 and Usherin. In the absence of an experimentally determined structure, homology modeling and threading often provide a useful 3D model of a protein. Therefore in the current study Clarin-1 and GPR98 proteins have been analyzed for signal peptide, domains and motifs. Clarin-1 protein was found to be without any signal peptide and consists of prokar lipoprotein domain. Clarin-1 is classified within claudin 2 super family and consists of twelve motifs. Whereas, GPR98 has a 29 amino acids long signal peptide and classified within GPCR family 2 having Concanavalin A-like lectin/glucanase superfamily. It was found to be consists of GPS and G protein receptor F2 domains and twenty nine motifs. Their 3D structures have been predicted using I-TASSER server. The model of Clarin-1 showed only α-helix but no beta sheets while model of GPR98 showed both α-helix and β sheets. The predicted structures were then evaluated and validated by MolProbity and Ramachandran plot. The evaluation of the predicted structures showed 78.9% residues of Clarin-1 and 78.9% residues of GPR98 within favored regions. The findings of present study has resulted in the three dimensional structure prediction and conserved domain analysis which will be quite beneficial in better understanding of molecular components, protein-protein interaction, clinical heterogeneity and pathophysiology of Usher syndrome.

Dataset Information

A novel homozygous variant of GPR98 causes usher syndrome type IIC in a consanguineous Chinese family by next generation sequencing.

Publications

A novel homozygous variant of GPR98 causes usher syndrome type IIC in a consanguineous Chinese family by next generation sequencing.

Similar Datasets

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