title: Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7.
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.
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Schil
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Karlstetter
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Aslanidis
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Dannhausen
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.
authors.forename: Maleeha
authors.initials: M
authors.lastname: Azam
authors.affiliation: Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.|Al-Nafees Medical College &Hospital, Isra University, Islamabad, Pakistan.|Pakistan Academy of Sciences, Islamabad, Pakistan.
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.|Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.|Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Department of Ophthalmology, Brugmann University Hospital, Brussels, Belgium.
authors.forename: Fanny
authors.initials: F
authors.lastname: Depasse
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langmann
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D011247:Pregnancy; D000072417:Protein Domains; D020218:Response Elements; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014421:Turkey
chemical_list: D018398:Homeodomain Proteins; D015534:Trans-Activators; C109288:cone rod homeobox protein; D012243:Rhodopsin