title: Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa.
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.
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030-3411, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030-3411, USA.
authors.forename: Smriti A
authors.initials: SA
authors.lastname: Agrawal
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030-3411, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030-3411, USA.
authors.forename: Aiden
authors.initials: A
authors.lastname: Eblimit
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bellingham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030-3411, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030-3411, USA.
authors.forename: Mingchu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030-3411, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030-3411, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Chakarova
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Parfitt
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Amelia
authors.initials: A
authors.lastname: Lane
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Burgoyne
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hull
authors.affiliation: NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge CB2 0PT, UK.
authors.forename: Keren J
authors.initials: KJ
authors.lastname: Carss
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fiorentino
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hayes
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Munro
authors.affiliation: Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030-3411, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Nicols
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Pontikos
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030-3411, USA.
authors.forename: Chinwe
authors.initials: C
authors.lastname: Asomugha
authors.affiliation: NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK; Ophthalmology Department, UCSF School of Medicine, Koret Vision Center, San Francisco, CA 94133-0644, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: UCL Genetics Institute, University College London, London WC1E 6BT, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hardcastle
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030-3411, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030-3411, USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Eye Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cukras
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK. Electronic address: michael.cheetham@ucl.ac.uk.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030-3411, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030-3411, USA. Electronic address: ruichen@bcm.edu.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000483:Alleles; D000818:Animals; D002648:Child; D002675:Child, Preschool; D005136:Eye Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D008297:Male; D008565:Membrane Proteins; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics*; D055815:Young Adult
chemical_list: D005136:Eye Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C000619079:REEP6 protein, human; C000602312:REEP6 protein, mouse