Three novel and the common Arg677Ter RP1 protein truncating mutations causing autosomal dominant retinitis pigmentosa in a Spanish population.

María José Gamundi,Miquel Maseras,Guillermo Antiñolo,Blanca García-Sandoval,Montserrat Baiget,María Martínez-Gimeno,Miguel Carballo,Carmen Ayuso,Imma Hernan

doi:10.1186/1471-2350-7-35

Abstract

BackgroundRetinitis pigmentosa (RP), a clinically and genetically heterogeneous group of retinal degeneration disorders affecting the photoreceptor cells, is one of the leading causes of genetic blindness. Mutations in the photoreceptor-specific gene RP1 account for 3–10% of cases of autosomal dominant RP (adRP). Most of these mutations are clustered in a 500 bp region of exon 4 of RP1.MethodsDenaturing gradient gel electrophoresis (DGGE) analysis and direct genomic sequencing were used to evaluate the 5' coding region of exon 4 of the RP1 gene for mutations in 150 unrelated index adRP patients. Ophthalmic and electrophysiological examination of RP patients and relatives according to pre-existing protocols were carried out.ResultsThree novel disease-causing mutations in RP1 were detected: Q686X, K705fsX712 and K722fsX737, predicting truncated proteins. One novel missense mutation, Thr752Met, was detected in one family but the mutation does not co-segregate in the family, thereby excluding this amino acid variation in the protein as a cause of the disease. We found the Arg677Ter mutation, previously reported in other populations, in two independent families, confirming that this mutation is also present in a Spanish population.ConclusionMost of the mutations reported in the RP1 gene associated with adRP are expected to encode mutant truncated proteins that are approximately one third or half of the size of wild type protein. Patients with mutations in RP1 showed mild RP with variability in phenotype severity. We also observed several cases of non-penetrant mutations.

Highlights

Retinitis pigmentosa (RP), a clinically and genetically heterogeneous group of retinal degeneration disorders affecting the photoreceptor cells, is one of the leading causes of genetic blindness
The major contribution in a Spanish population is due to rhodopsin mutations (19.5 %), with the rest of the specific genes expressed in the retina less than 4% [unpublished results] More recently, mutations in the ubiquitously expressed pre-mRNA splicing factor genes PRPF3, PRPF8, PRPF31 or in the IMPDH1 gene have been associated with autosomal dominant RP (adRP) [10,11,12,13]
Three Polymerase Chain Reaction (PCR)-amplified fragments from DNA of the 150 index patients of adRP Spanish families and 100 controls were analyzed by Denaturing gradient gel electrophoresis (DGGE)

Summary

Introduction

Retinitis pigmentosa (RP), a clinically and genetically heterogeneous group of retinal degeneration disorders affecting the photoreceptor cells, is one of the leading causes of genetic blindness. Mutations in the photoreceptor-specific gene RP1 account for 3–10% of cases of autosomal dominant RP (adRP). Most of these mutations are clustered in a 500 bp region of exon 4 of RP1. Autosomal dominant retinitis pigmentosa (adRP) accounts for 25– 30% of all Spanish RP patients (unpublished data). The major contribution in a Spanish population is due to rhodopsin mutations (19.5 %), with the rest of the specific genes expressed in the retina less than 4% [unpublished results] More recently, mutations in the ubiquitously expressed pre-mRNA splicing factor genes PRPF3, PRPF8, PRPF31 or in the IMPDH1 gene have been associated with adRP [10,11,12,13]. The contribution of mutations in these genes is above 8% in a Spanish population [unpublished results]

Methods

Results

Discussion

Conclusion