Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa. Arno, G., Agrawal, S. A., Eblimit, A., Bellingham, J., Xu, M., Wang, F., Chakarova, C., Parfitt, D. A., Lane, A., Burgoyne, T., Hull, S., Carss, K. J., Fiorentino, A., Hayes, M. J., Munro, P. M., Nicols, R., Pontikos, N., Holder, G. E., UKIRDC, Asomugha, C., Raymond, F. L., Moore, A. T., Plagnol, V., Michaelides, M., Hardcastle, A. J., Li, Y., Cukras, C., Webster, A. R., Cheetham, M. E., & Chen, R. American Journal of Human Genetics, 99(6):1305–1315, December, 2016.
doi  abstract   bibtex   
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\textgreaterT [p.Pro128Leu] and c.404T\textgreaterC [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.
@article{arno_mutations_2016,
	title = {Mutations in {REEP6} {Cause} {Autosomal}-{Recessive} {Retinitis} {Pigmentosa}},
	volume = {99},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2016.10.008},
	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{\textgreater}T [p.Pro128Leu] and c.404T{\textgreater}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.},
	language = {eng},
	number = {6},
	journal = {American Journal of Human Genetics},
	author = {Arno, Gavin and Agrawal, Smriti A. and Eblimit, Aiden and Bellingham, James and Xu, Mingchu and Wang, Feng and Chakarova, Christina and Parfitt, David A. and Lane, Amelia and Burgoyne, Thomas and Hull, Sarah and Carss, Keren J. and Fiorentino, Alessia and Hayes, Matthew J. and Munro, Peter M. and Nicols, Ralph and Pontikos, Nikolas and Holder, Graham E. and {UKIRDC} and Asomugha, Chinwe and Raymond, F. Lucy and Moore, Anthony T. and Plagnol, Vincent and Michaelides, Michel and Hardcastle, Alison J. and Li, Yumei and Cukras, Catherine and Webster, Andrew R. and Cheetham, Michael E. and Chen, Rui},
	month = dec,
	year = {2016},
	pmid = {27889058},
	pmcid = {PMC5142109},
	keywords = {Adolescent, Alleles, Animals, Child, Child, Preschool, Eye Proteins, Female, Genes, Recessive, Humans, Induced Pluripotent Stem Cells, Male, Membrane Transport Proteins, Mice, Mutation, Mutation, Missense, Phenotype, Photoreceptor Cells, Vertebrate, Retinitis Pigmentosa, Young Adult},
	pages = {1305--1315}
}
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