Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration
| Autor: | Chris F. Inglehearn, Huidan Xu, Rui Chen, Hussain Jafri, Yasmin Rashid, Moin Mohamed, Colin A. Johnson, Jingliang Cheng, Graham R. Taylor, Mohammed Nageeb, Yiyun Chen, Clare V. Logan, Vafa Keser, Martin McKibbin, Jacek Majewski, Bruce E. Hayward, Mohammed Genead, Xia Wang, Huanan Ren, Carmel Toomes, Qing Fu, Yumei Li, Elias I. Traboulsi, David A. Parry, Gerald A. Fishman, Irma Lopez, Hui Wang, Graeme Mardon, James A. Poulter, Jeremy Schwartzentruber, Naimesh Solanki, Robert K. Koenekoop |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Nature Genetics. 44:1035-1039 |
| ISSN: | 1546-1718 1061-4036 |
| Popis: | Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wlds) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder. |
| Databáze: | OpenAIRE |
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