Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa PMID: 27889058

Target-related Cytokines

2026-09-23

Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa

Am J Hum Genet. 2016 Dec 1;99(6):1305-1315. doi: 10.1016/j.ajhg.2016.10.008.

Gavin Arno ¹ , Smriti A Agrawal ² , Aiden Eblimit ² , James Bellingham ³ , Mingchu Xu ² , Feng Wang ² , Christina Chakarova ³ , David A Parfitt ³ , Amelia Lane ³ , Thomas Burgoyne ³ , Sarah Hull ¹ , Keren J Carss ⁴ , Alessia Fiorentino ³ , Matthew J Hayes ³ , Peter M Munro ³ , Ralph Nicols ⁵ , Nikolas Pontikos ³ , Graham E Holder ¹ , UKIRDC , Chinwe Asomugha ⁶ , F Lucy Raymond ⁷ , Anthony T Moore ⁸ , Vincent Plagnol ⁹ , Michel Michaelides ¹ , Alison J Hardcastle ³ , Yumei Li ² , Catherine Cukras ¹⁰ , Andrew R Webster ¹ , Michael E Cheetham ¹¹ , Rui Chen ¹²

Affiliations

1. UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
2. 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.
3. UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
4. 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.
5. Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030-3411, USA.
6. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030-3411, USA.
7. 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.
8. 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.
9. UCL Genetics Institute, University College London, London WC1E 6BT, UK.
10. National Eye Institute, NIH, Bethesda, MD 20892, USA.
11. UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK. Electronic address: [email protected].
12. 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: [email protected].

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.