Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7

• Published in: Scientific reports 2016-02, Vol.6 (1), p.21307-21307, Article 21307
• Main Authors: Van Schil, Kristof, Karlstetter, Marcus, Aslanidis, Alexander, Dannhausen, Katharina, Azam, Maleeha, Qamar, Raheel, Leroy, Bart P., Depasse, Fanny, Langmann, Thomas, De Baere, Elfride
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/109; 38/44; 45/23; 45/77; 631/208/1397; 631/208/200; 631/208/737; 692/1807/1482; 692/308/2056; Amino Acid Substitution; Animals; Electroporation; Explants; Female; Gene mapping; Genetic Diseases, Inborn - genetics; Genetic Diseases, Inborn - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Humans; Male; Mice; multidisciplinary; Mutation; Mutation, Missense; Pigmentation; Pregnancy; Protein Domains; Regulatory sequences; Response Elements; Retina; Retinitis; Retinitis pigmentosa; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - metabolism; Rhodopsin; Rhodopsin - genetics; Rhodopsin - metabolism; Science; Siblings; Trans-Activators - genetics; Trans-Activators - metabolism; Turkey
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep21307

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.