Abstract
Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy.
Highlights
Retinitis pigmentosa (RP [MIM: 268000]) is the most common inherited retinal dystrophy, affecting approximately 1 in 4,000 individuals[1] and resulting in more than 1 million visually impaired individuals worldwide
A simplex RP individual (A-II:1), an Asian male from a non-consanguineous family, and individual B-II:[8], one of three male siblings with RP born to consanguineous parents of African descent, were selected for whole-exome sequencing (WES) after negative screening by targeted capture sequencing of 226 and 176 genes known to harbor pathogenic mutations associated with inherited retinal disease, respectively
For individual A-II:[1], based on the presumed recessive inheritance, genes with two or more variants were prioritized and variants were excluded in genes if at least one of the variants was predicted to be benign or neutral by at least 4/5 of the algorithms used, or if homozygous loss-of-function (LOF) genotype was observed in the Exome Aggregation Consortium (ExAC) database (Table S1)
Summary
Retinitis pigmentosa (RP [MIM: 268000]) is the most common inherited retinal dystrophy, affecting approximately 1 in 4,000 individuals[1] and resulting in more than 1 million visually impaired individuals worldwide. RP is genetically heterogeneous with autosomal-dominant, autosomal-recessive, and X-linked modes of inheritance and at least 58 genes associated with an autosomal-recessive form (arRP; RetNet). These genes encode proteins involved in a diverse range of functional pathways in the neural retina including photoreceptor development, phototransduction, retinoid cycle, cilia, and outer segment development and protein transport.[2,3] Mutations in any one of these many pathways leads to a remarkably similar phenotype characterized by rod photoreceptor dysfunction and degeneration and subsequent cone degeneration.[4,5] Affected individuals commonly present with nyctalopia and peripheral visual field constriction; there can be severe vision loss if the macular cones become involved. Despite the development of targeted next-generation sequencing screening strategies for identifying pathogenic variants in genes already associated with RP, an estimated 40% of cases remain without a molecular diagnosis,[6] suggesting that mutations may exist in genes not previously associated with Mendelian disease
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