Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa.

TitleMutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa.
Publication TypeJournal Article
Year of Publication2016
AuthorsArno, G, Agrawal, SA, Eblimit, A, Bellingham, J, Xu, M, Wang, F, Chakarova, C, Parfitt, DA, Lane, A, Burgoyne, T, Hull, S, Carss, KJ, Fiorentino, A, Hayes, MJ, Munro, PM, Nicols, R, Pontikos, N, Holder, GE, Asomugha, C, F Raymond, L, Moore, AT, Plagnol, V, Michaelides, M, Hardcastle, AJ, Li, Y, Cukras, C, Webster, AR, Cheetham, ME, Chen, R
Corporate AuthorsUKIRDC
JournalAm J Hum Genet
Date Published2016 Dec 01
KeywordsAdolescent, Alleles, Animals, Child, Child, Preschool, Eye Proteins, Female, Genes, Recessive, Humans, Induced Pluripotent Stem Cells, Male, Membrane Proteins, Membrane Transport Proteins, Mice, Mutation, Mutation, Missense, Phenotype, Photoreceptor Cells, Vertebrate, Retinitis Pigmentosa, Young Adult

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.

Alternate JournalAm J Hum Genet
PubMed ID27889058
PubMed Central IDPMC5142109
Grant ListR01 EY020540 / EY / NEI NIH HHS / United States
MC_PC_15018 / MRC_ / Medical Research Council / United Kingdom
R01 EY022356 / EY / NEI NIH HHS / United States
P30 EY002520 / EY / NEI NIH HHS / United States
/ / Wellcome Trust / United Kingdom

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