Abstract
Purpose. To investigate genetic and clinical features of patients with rhodopsin (RHO) mutations in two Japanese families with autosomal dominant retinitis pigmentosa (adRP). Methods. Whole-exome sequence analysis was performed in ten adRP families. Identified RHO mutations for the cosegregation analysis were confirmed by Sanger sequencing. Ophthalmic examinations were performed to evaluate the RP phenotypes. The impact of the RHO mutation on the rhodopsin conformation was examined by molecular modeling analysis. Results. In two adRP families, we identified two RHO mutations (c.377G>T (p.W126L) and c.1036G>C (p.A346P)), one of which was novel. Complete cosegregation was confirmed for each mutation exhibiting the RP phenotype in both families. Molecular modeling predicted that the novel mutation (p.W126L) might impair rhodopsin function by affecting its conformational transition in the light-adapted form. Clinical phenotypes showed that patients with p.W126L exhibited sector RP, whereas patients with p.A346P exhibited classic RP. Conclusions. Our findings demonstrated that the novel mutation (p.W126L) may be associated with the phenotype of sector RP. Identification of RHO mutations is a very useful tool for predicting disease severity and providing precise genetic counseling.
Highlights
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders characterized by night blindness, constricted visual fields, abnormal color vision, and retinal degeneration
We identified two RHO mutations (p.W126L and p.A346P) as disease causes by using whole-exome sequencing in two Japanese families with Autosomal dominant RP (adRP)
We used molecular modeling to analyze the impact of the novel mutation (p.W126L) on the protein structure and function and evaluated the genotype-phenotype correlations among Japanese RP patients with heterozygous RHO mutations
Summary
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders characterized by night blindness, constricted visual fields, abnormal color vision, and retinal degeneration. Autosomal dominant RP (adRP) makes up 30 to 40% of the overall RP cases, while mutations in the rhodopsin (RHO). Gene are responsible for about 25% of adRP cases found in Caucasians [1]. The RHO gene has been mapped to the long arm of chromosome 3 (3p21-24) and encodes 348 amino acids [4]. In 1990, the RHO gene was first described in the literature as being the causative gene for adRP [5, 6]. When rhodopsin absorbs the photon, retinal chromophore (11-cis-retinal) changes to all-trans-retinal. The conformational changes that occur in rhodopsin result in the hyperpolarization of the rod cells, which play an important role in vision [7]
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