Dataset Information

Identification of 13 novel USH2A mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing.

ABSTRACT: BACKGROUND:The USH2A gene encodes usherin, a basement membrane protein that is involved in the development and homeostasis of the inner ear and retina. Mutations in USH2A are linked to Usher syndrome type II (USH II) and non-syndromic retinitis pigmentosa (RP). Molecular diagnosis can provide insight into the pathogenesis of these diseases, facilitate clinical diagnosis, and identify individuals who can most benefit from gene or cell replacement therapy. Here, we report 21 pathogenic mutations in the USH2A gene identified in 11 Chinese families by using the targeted next-generation sequencing (NGS) technology. METHODS:In all, 11 unrelated Chinese families were enrolled, and NGS was performed to identify mutations in the USH2A gene. Variant analysis, Sanger validation, and segregation tests were utilized to validate the disease-causing mutations in these families. RESULTS:We identified 21 pathogenic mutations, of which 13, including 5 associated with non-syndromic RP and 8 with USH II, have not been previously reported. The novel variants segregated with disease phenotype in the affected families and were absent from the control subjects. In general, visual impairment and retinopathy were consistent between the USH II and non-syndromic RP patients with USH2A mutations. CONCLUSIONS:These findings provide a basis for investigating genotype-phenotype relationships in Chinese USH II and RP patients and for clarifying the pathophysiology and molecular mechanisms of the diseases associated with USH2A mutations.

SUBMITTER: Qu LH

PROVIDER: S-EPMC6974426 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Identification of 13 novel USH2A mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing.

Qu Ling-Hui LH Jin Xin X Long Yan-Ling YL Ren Jia-Yun JY Weng Chuang-Huang CH Xu Hai-Wei HW Liu Yong Y Meng Xiao-Hong XH Li Shi-Ying SY Yin Zheng-Qin ZQ

Bioscience reports 20200101 1

<h4>Background</h4>The USH2A gene encodes usherin, a basement membrane protein that is involved in the development and homeostasis of the inner ear and retina. Mutations in USH2A are linked to Usher syndrome type II (USH II) and non-syndromic retinitis pigmentosa (RP). Molecular diagnosis can provide insight into the pathogenesis of these diseases, facilitate clinical diagnosis, and identify individuals who can most benefit from gene or cell replacement therapy. Here, we report 21 pathogenic mut ...[more]

PMID: 31904091

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Project description:BackgroundRetinitis pigmentosa (RP) is one of the major types of hereditary retinal dystrophies with extreme genotypic heterogeneity. To date, more than 80 genes have been identified to be associated with RP in human.MethodHere, we presented a clinical genetic study of three Chinese man manifested with night vision blindness and complete loss of midperipheral visual field. All of these three probands have been identified with loss of both central vision and far peripheral visual field. Gradual loss of rod cells followed by subsequent loss of cone cells have been identified in these probands. Targeted next generation sequencing and Sanger sequencing have been performed to understand the pathogenic variants underlying the disease phenotype in these three unrelated Chinese probands.ResultsTargeted next generation sequencing and Sanger sequencing identified three homozygous novel mutations (c.1880C>A; c.1459_1460delGA, and c.392G>A) in the MERTK gene in these three unrelated Chinese proband. In the first proband, the identified mutation (c.1880C>A) leads to the formation of a premature stop codon followed by the formation of a truncated mer-tyrosine kinase (MERTK) protein (p.Ser627*) product which predicted to be disease causing. In the second proband, the identified deletion (c.1459_1460delGA) leads to the formation of a frameshift which also finally results in the formation of a truncated MERTK protein (p.Asp487Leufs*57) product which also predicted to be disease causing. In the third proband, the identified mutation (c.392G>A) leads to the formation of a premature stop codon followed by the formation of a truncated MERTK protein (p.Trp131*) product which also predicted to be disease causing. Hence, these three mutations are loss-of-function mutations. These three mutations were absent in unaffected family members and in 100 normal healthy controls.ConclusionOur present study also demonstrates the significance of targeted next generation sequencing in determining the genetic basis of RP.

Project description:PurposeTo describe the clinical and genetic findings in one Chinese family with autosomal recessive retinitis pigmentosa (arRP) and in three unrelated Chinese families with Usher syndrome type II (USH2).MethodsOne family (FR1) with arRP and three unrelated families (F6, F7, and F8) with Usher syndrome (USH), including eight affected members and seven unaffected family individuals were examined clinically. The study included 100 normal Chinese individuals as normal controls. After obtaining informed consent, peripheral blood samples from all participants were collected and genomic DNA was extracted. Genotyping and haplotyping analyses were performed on the known genetic loci for arRP with a panel of polymorphic markers in family FR1. In all four families, the coding region (exons 2-72), including the intron-exon boundary of the USH2A (Usher syndrome type -2A protein) gene, was screened by PCR and direct DNA sequencing. Whenever substitutions were identified in a patient, a restriction fragment length polymorphism (RFLP) analysis, single strand conformation polymorphism (SSCP) analysis, or high resolution melt curve analysis (HRM) was performed on all available family members and on the 100 normal controls.ResultsThe affected individuals presented with typical fundus features of retinitis pigmentosa (RP), including narrowing of the vessels, bone-spicule pigmentation, and waxy optic discs. The electroretinogram (ERG) wave amplitudes of the available probands were undetectable. Audiometric tests in the affected individuals in family FR1 were normal, while indicating moderate to severe sensorineural hearing impairment in the affected individuals in families F6, F7, and F8. Vestibular function was normal in all patients from all four families. The disease-causing gene in family FR1 was mapped to the USH2A locus on chromosome 1q41. Seven novel mutations (two missenses, one 7-bp deletion, two small deletions, and two nonsenses) were detected in the four families after sequencing analysis of USH2A.ConclusionsThe results further support that mutations of USH2A are also responsible for non-syndromic RP. The mutation spectrum among Chinese patients might differ from that among European Caucasians.

Dataset Information

Identification of 13 novel USH2A mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing.

Publications

Identification of 13 novel USH2A mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing.

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