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Carlo Rivolta, Paola Benaglio, Tremeur Guillaumie, Gael Manes, Shyana Harper, Eliot L Berson, Isabelle Meunier, Christian P Hamel; Molecular characterization of SNRNP200 mutations causing autosomal dominant retinitis pigmentosa with incomplete penetrance and phenotypic variability. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3264.
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Mutations in splicing factor genes have been linked to autosomal dominant retinitis pigmentosa (adRP). In some instances, and mostly for mutations in the splicing factor gene PRPF31, dominant inheritance with incomplete penetrance is observed. Following the identification of a family with adRP with incomplete penetrance and a mutation in the splicing factor gene SNRNP200, we performed clinical and molecular characterization of eight cases presenting with heterozygous mutations in this gene.
Clinical assessment of RP was performed by ophthalmological examination, including ERG. DNA screening was carried out by exon-PCRs and Sanger sequencing. For 4 patients, we obtained lymphoblastoid cell lines following immortalization of circulating lymphocytes with the Epstein-Barr virus. Gene expression was tested by relative and allele-specific qPCR, at the steady state and after actinomycin treatment. Protein levels were estimated by Western Blot.
We identified the recurrent p.Arg681Cys mutation in SNRNP200 in a 4-generation French family with RP. In this pedigree, two siblings and their great-grandmother were affected, while their mother and grandmother carried the mutation but had no signs of RP, including normal ERG responses. Intra-familial variability of RP phenotypes was also observed: the great-grandmother and one of the two siblings were severely affected, while the second sibling had only moderate signs of retinal degeneration. We also evaluated 4 unrelated American RP patients carrying p.Arg681Cys, p.Arg681His and p.Ser1087Leu SNRNP200 mutations and 2 healthy controls. Phenotypic variability was also observed in the American patients. No consistent differences in gene or allele-specific expression were detected within the analyzed family, as well as compared to unrelated patients and controls. Similar results were obtained when analyzing the total protein abundance.
We investigated possible molecular mechanisms underlying incomplete penetrance and variable expressivity of the heterozygous p.Arg681Cys mutation in the SNRNP200 splicing factor gene. The absence of detectable differences in gene expression excluded a mechanism based on gene dosage compensation, unlike the case of PRPF31 mutations with reduced penetrance. Clinically, SNRNP200 mutations seem to cause a form of adRP with definite phenotypic variability.
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