Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7
نویسندگان
چکیده
The aim of this study was to unravel the molecular pathogenesis of an unusual retinitis pigmentosa (RP) phenotype observed in a Turkish consanguineous family. Homozygosity mapping revealed two candidate genes, SAMD7 and RHO. A homozygous RHO mutation c.448G > A, p.E150K was found in two affected siblings, while no coding SAMD7 mutations were identified. Interestingly, four non-coding homozygous variants were found in two SAMD7 genomic regions relevant for binding of the retinal transcription factor CRX (CRX-bound regions, CBRs) in these affected siblings. Three variants are located in a promoter CBR termed CBR1, while the fourth is located more downstream in CBR2. Transcriptional activity of these variants was assessed by luciferase assays and electroporation of mouse retinal explants with reporter constructs of wild-type and variant SAMD7 CBRs. The combined CBR2/CBR1 variant construct showed significantly decreased SAMD7 reporter activity compared to the wild-type sequence, suggesting a cis-regulatory effect on SAMD7 expression. As Samd7 is a recently identified Crx-regulated transcriptional repressor in retina, we hypothesize that these SAMD7 variants might contribute to the retinal phenotype observed here, characterized by unusual, recognizable pigment deposits, differing from the classic spicular intraretinal pigmentation observed in other individuals homozygous for p.E150K, and typically associated with RP in general.
منابع مشابه
Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization.
The pathophysiology of the E150K mutation in the rod opsin gene associated with autosomal recessive retinitis pigmentosa (arRP) has yet to be determined. We generated knock-in mice carrying a single nucleotide change in exon 2 of the rod opsin gene resulting in the E150K mutation. This novel mouse model displayed severe retinal degeneration affecting rhodopsin's stabilization of rod outer segme...
متن کاملElectrostatic compensation restores trafficking of the autosomal recessive retinitis pigmentosa E150K opsin mutant to the plasma membrane.
Rhodopsin is the rod photoreceptor G protein-coupled receptor responsible for capturing light. Mutations in the gene encoding this protein can lead to a blinding disease called retinitis pigmentosa, which is inherited frequently in an autosomal dominant manner. The E150K opsin mutant associated with rarely occurring autosomal recessive retinitis pigmentosa localizes to trans-Golgi network membr...
متن کاملGenomic screening of ABCA4 and array CGH analysis underline the genetic variability of Greek patients with inherited retinal diseases
BACKGROUND Retinal dystrophies are a clinically and genetically heterogeneous group of disorders which affect more than two million people worldwide. The present study focused on the role of the ABCA4 gene in the pathogenesis of hereditary retinal dystrophies (autosomal recessive Stargardt disease, autosomal recessive cone-rod dystrophy, and autosomal recessive retinitis pigmentosa) in patients...
متن کاملIdentification of a novel nonsense mutation in RP1 that causes autosomal recessive retinitis pigmentosa in an Indonesian family
PURPOSE The purpose of this study was to identify the underlying molecular genetic defect in an Indonesian family with three affected individuals who had received a diagnosis of retinitis pigmentosa (RP). METHODS Clinical evaluation of the family members included measuring visual acuity and fundoscopy, and assessing visual field and color vision. Genomic DNA of the three affected individuals ...
متن کاملScreening of the MERTK gene for mutations in Japanese patients with autosomal recessive retinitis pigmentosa.
PURPOSE To determine whether mutations in the MERTK gene are present in Japanese patients with autosomal recessive retinitis pigmentosa (arRP). METHODS The coding sequence of all 19 exons and the adjacent flanking intron sequences of the MERTK gene were directly sequenced in 96 unrelated Japanese patients with arRP. RESULTS Seventeen sequence variants were found; six missense changes, three...
متن کامل