Abstract
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.
Highlights
The aim of this study was to unravel the molecular pathogenesis of an unusual retinitis pigmentosa (RP) phenotype observed in a Turkish consanguineous family
Several examples of non-coding mutations in such elements have been reported in retinal dystrophies (RDs), including a deletion of the first non-coding exon of EYS25, LCA526 and PCDH1527 containing the promoter of the gene; a non-coding mutation in the first non-coding exon of EYS25; mutations in the 5′ untranslated region of NMNAT128, deep intronic variants in the ABCA429–31, OFD132, CEP29033, USH2A34 and PROM135 genes leading to alternate splicing; and a mutation in the seed region of microRNA-20436, and very recently variations in a DNase I hypersensitivity site upstream of PRDM1337
The aim of this study was to unravel the molecular pathogenesis of an atypical retinitis pigmentosa phenotype (RP) observed in a Turkish consanguineous family
Summary
The aim of this study was to unravel the molecular pathogenesis of an unusual retinitis pigmentosa (RP) phenotype observed in a Turkish consanguineous family. One strategy that has been shown to be effective is the use of a Crx-based cis-regulatory dataset[13,17,18] This dataset consists of a genome-wide map of binding regions of the key retinal transcription factor Crx thereby identifying genes that are regulated by this transcription factor[17]. One of these genes is Samd[7] (sterile alpha motif domain containing 7), which is highly expressed in the adult murine retina and localizes to the outer nuclear layer of the retina, containing the photoreceptor nuclei[17,19]. Several examples of non-coding mutations in such elements have been reported in RD, including a deletion of the first non-coding exon of EYS25, LCA526 and PCDH1527 containing the promoter of the gene; a non-coding mutation in the first non-coding exon of EYS25; mutations in the 5′ untranslated region of NMNAT128, deep intronic variants in the ABCA429–31, OFD132, CEP29033, USH2A34 and PROM135 genes leading to alternate splicing; and a mutation in the seed region of microRNA-20436, and very recently variations in a DNase I hypersensitivity site upstream of PRDM1337
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