Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 99, Issue 6, Pages 1305-1315Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2016.10.008
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Funding
- Foundation Fighting Blindness [BR-GE-0613-0618-BCM]
- National Eye Institute [R01EY022356, R01EY020540]
- NEI vision core grant [P30EY002520]
- RP Fighting Blindness and Fight for Sight
- Wellcome Trust [092621]
- National Institute for Health Research (UK)
- Biomedical Research Centre at Moorfields Eye Hospital
- UCL Institute of Ophthalmology
- Fight for Sight UK
- Moorfields Eye Hospital Special Trustees
- Foundation Fighting Blindness - USA
- Fight for Sight [1511/12] Funding Source: researchfish
- Medical Research Council [1125070] Funding Source: researchfish
- National Institute for Health Research [ACF-2013-06-009] Funding Source: researchfish
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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.
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