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Two novel PRP31 premessenger ribonucleic acid processing factor 31 homolog mutations including a complex insertion-deletion identified in Chinese families with retinitis pigmentosa.

ABSTRACT: OBJECTIVE: To identify the causative mutations in two Chinese families with retinitis pigmentosa (RP), and to describe the associated phenotype. METHODS: Individuals from two unrelated families underwent full ophthalmic examinations. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Linkage analysis was performed on the known genetic loci for autosomal dominant retinitis pigmentosa with a panel of polymorphic markers in the two families, and then all coding exons of the PRP31 premessenger ribonucleic acid processing factor 31 homolog (PRPF31) gene were screened for mutations with direct sequencing of PCR-amplified DNA fragments. Allele-specific PCR was used to validate a substitution in all available family members and 100 normal controls. A large deletion was detected with real-time quantitative PCR (RQ-PCR) using a panel of primers from regions around the PRPF31 gene. Long-range PCR, followed by DNA sequencing, was used to define the breakpoints. RESULTS: Clinical examination and pedigree analysis revealed two four-generation families (RP24 and RP106) with autosomal dominant retinitis pigmentosa. A significant two-point linkage odd disequilibrium score was generated at marker D19S926 (Zmax=3.55, ?=0) for family RP24 and D19S571 (Zmax=3.21, ?=0) for family RP106, and further linkage and haplotype studies confined the disease locus to chromosome 19q13.42 where the PRPF31 gene is located. Mutation screening of the PRPF31 gene revealed a novel deletion c.1215delG (p.G405fs+7X) in family RP106. The deletion cosegregated with the family's disease phenotype, but was not found in 100 normal controls. No disease-causing mutation was detected in family RP24 with PCR-based sequencing analysis. RQ-PCR and long-range PCR analysis revealed a complex insertion-deletion (indel) in the patients of family RP24. The deletion is more than 19 kb and encompasses part of the PRPF31 gene (exons 1-3), together with three adjacent genes. CONCLUSIONS: Our results further confirmed that haploinsufficiency is the main mechanism for RP11 and that genomic arrangements may be prevalent in PRPF31 mutations.

SUBMITTER: Dong B

PROVIDER: S-EPMC3850970 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Two novel PRP31 premessenger ribonucleic acid processing factor 31 homolog mutations including a complex insertion-deletion identified in Chinese families with retinitis pigmentosa.

Dong Bing B Chen Jieqiong J Zhang Xiaohui X Pan Zhe Z Bai Fengge F Li Yang Y

Molecular vision 20131122

<h4>Objective</h4>To identify the causative mutations in two Chinese families with retinitis pigmentosa (RP), and to describe the associated phenotype.<h4>Methods</h4>Individuals from two unrelated families underwent full ophthalmic examinations. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Linkage analysis was performed on the known genetic loci for autosomal dominant retinitis pigmentosa with a panel of polymorphic markers in the two ...[more]

PMID: 24319336

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Project description:PURPOSE: Retinitis pigmentosa (RP; MIM 268000) is a hereditary disease characterized by poor night vision and progressive loss of photoreceptors, eventually leading to blindness. This degenerative process primarily affects peripheral vision due to the loss of rods. Autosomal recessive RP (arRP) is clinically and genetically heterogeneous. It has been associated with mutations in different genes, including CRB1 (crumbs homolog 1). The aim of this study was to determine the causative gene in a Tunisian patient with arRP born to non-consanguineous parents. METHODS: Four accessible family members were included. They underwent full ophthalmic examination with best-corrected Snellen visual acuity, fundus photography and fluorescein angiography. Haplotype analysis was used to evaluate homozygosity in the family to 20 arRP loci. All exons and intron-exon junctions of candidate genes not excluded by haplotype analysis were PCR amplified and directly sequenced. RESULTS: The proband was a 43-year-old female patient. Best-corrected visual acuity was 20/63 (right eye) and 20/80 (left eye). Visual loss began during the third decade. Funduscopic examination and fluorescein angiography revealed typical advanced RP changes with bone spicule-like pigment deposits in the posterior pole and the midperiphery along with retinal atrophy, narrowing of the vessels, and waxy optic discs. Haplotype analysis revealed homozygosity with microsatellite markers D1S412 and D1S413 on chromosome 1q31.3. These markers flanked CRB1. Our results excluded linkage of all the other arRP loci/genes tested. Sequencing of the 12 coding exons and splice sites of CRB1 disclosed a homozygous missense mutation in exon 7 at nucleotide c. 2291G>A, resulting in an arginine to histidine substitution (p.R764H). CONCLUSIONS: R764H is a novel mutation associated with CRB1-related arRP. Previously, an R764C mutation was reported. Extending the mutation spectrum of CRB1 with additional families is important for genotype-phenotype correlations and characterization of the scope of mutation.

Dataset Information

Two novel PRP31 premessenger ribonucleic acid processing factor 31 homolog mutations including a complex insertion-deletion identified in Chinese families with retinitis pigmentosa.

Publications

Two novel PRP31 premessenger ribonucleic acid processing factor 31 homolog mutations including a complex insertion-deletion identified in Chinese families with retinitis pigmentosa.

Similar Datasets

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