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Novel mutations in one allele in a Chinese family with neurofibromatosis type 1: Including a complex insertion-deletion mutation.

ABSTRACT: Neurofibromatosis type 1 (NF1) is a hereditary disease with variable clinical manifestations. This study was performed in a Chinese three-generation family containing two members with NF1. Two novel mutations, c.853_854insTC and c.1975_1976delinsTA, were identified in the same allele in both patients by direct sequencing. By reverse transcription polymerase chain reaction, we found that the NF1 transcript contained the first mutation instead of the second mutation, suggesting a pathological role of c.853_854insTC mutation. Case reports of patients with two NF1 mutations in the same allele have not been reported. Our findings expand the known spectrum of NF1 mutations and the ongoing recognition of different mutations may give insight into the mysterious NF1 pathogenesis.

SUBMITTER: Zhu L

PROVIDER: S-EPMC5108421 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Novel mutations in one allele in a Chinese family with neurofibromatosis type 1: Including a complex insertion-deletion mutation.

Zhu Lude L Shi Lei L Wang Bo B Bi Mingye M Pu Jie J Zhang Linglin L Zhang Yunfeng Y Wang Xiuli X Zhang Guolong G

The Journal of dermatology 20160704 11

Neurofibromatosis type 1 (NF1) is a hereditary disease with variable clinical manifestations. This study was performed in a Chinese three-generation family containing two members with NF1. Two novel mutations, c.853_854insTC and c.1975_1976delinsTA, were identified in the same allele in both patients by direct sequencing. By reverse transcription polymerase chain reaction, we found that the NF1 transcript contained the first mutation instead of the second mutation, suggesting a pathological role ...[more]

PMID: 27374410

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Project description:ObjectiveTo identify the causative mutations in two Chinese families with retinitis pigmentosa (RP), and to describe the associated phenotype.MethodsIndividuals 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.ResultsClinical 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, θ=0) for family RP24 and D19S571 (Zmax=3.21, θ=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.ConclusionsOur results further confirmed that haploinsufficiency is the main mechanism for RP11 and that genomic arrangements may be prevalent in PRPF31 mutations.

Project description:PURPOSE: Oguchi's disease is a rare autosomal recessive disease and known to be caused by mutations in the rhodopsin kinase (GRK1) gene or the arrestin (SAG) gene. SAG contains 16 exons and encodes a protein with 405 amino acids. This study was to identify the underlying genetic defects in a non-consanguineous Chinese family with Oguchi's disease. METHODS: Ophthalmologic examinations including fundus photography and electroretinography (ERG) were performed on all family members. All exons of the GRK1 gene and the SAG gene were amplified with PCR and directly sequenced. Quantitative real-time PCR (qPCR) was performed to screen heterozygous deletions/duplications in the SAG gene. Long-range PCR and direct sequencing were further performed to define the breakpoints. RESULTS: The patient had characteristic clinical features of Oguchi's disease, including night blindness, normal vision fields, typical fundus appearance with the Mizuo-Nakamura phenomenon, nearly undetectable rod b waves in the scotopic 0.01 ERGs, and nearly "negative" scotopic 3.0 ERGs. No mutations were found in the GRK1 gene. A heterozygous nonsense Arg193stop (R193X) mutation was found in the SAG gene in the patient and the unaffected mother. No pathogenic SAG mutations were found in the unaffected father. qPCRs showed a heterozygous deletion encompassing exon 2 of the SAG gene in the patient and the unaffected father. Long-range PCR and direct sequencing verified the deletion and revealed the breakpoints of the deletion, skipping a 3,224-bp fragment of the SAG gene. The deletion was not detected in 96 unrelated healthy controls. This deletion was predicted to eliminate the exon 2 and the AUG initiate codon in the mature SAG mRNA and cause no production of the SAG protein or low-level production of a non-functional truncated protein lacking 134 amino acids in the NH(2) terminus. CONCLUSIONS: Compound heterozygosity of a nonsense R193X mutation and a heterozygous deletion of 3,224 bp encompassing exon 2 in the SAG gene is the cause of Oguchi's disease in this Chinese family. qPCR analysis should be performed if there is a negative result of the mutation screening of the SAG gene in patients with Oguchi's disease.

Dataset Information

Novel mutations in one allele in a Chinese family with neurofibromatosis type 1: Including a complex insertion-deletion mutation.

Publications

Novel mutations in one allele in a Chinese family with neurofibromatosis type 1: Including a complex insertion-deletion mutation.

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