Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration

• Published in: Nature genetics Vol. 44; no. 9; pp. 1035 - 1039
• Main Authors: Koenekoop, Robert K, Wang, Hui, Majewski, Jacek, Wang, Xia, Lopez, Irma, Ren, Huanan, Chen, Yiyun, Li, Yumei, Fishman, Gerald A, Genead, Mohammed, Schwartzentruber, Jeremy, Solanki, Naimesh, Traboulsi, Elias I, Cheng, Jingliang, Logan, Clare V, McKibbin, Martin, Hayward, Bruce E, Parry, David A, Johnson, Colin A, Nageeb, Mohammed, Poulter, James A, Mohamed, Moin D, Jafri, Hussain, Rashid, Yasmin, Taylor, Graham R, Keser, Vafa, Mardon, Graeme, Xu, Huidan, Inglehearn, Chris F, Fu, Qing, Toomes, Carmel, Chen, Rui
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2012; Nature Publishing Group
• Subjects: 631/208/191; 631/208/2489/144; 692/699/375/365; Adolescent; Adult; Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedicine; Cancer Research; Cell culture; Child; Cohort Studies; Crystal structure; Development and progression; Disease; Family; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genetic aspects; Genetic Predisposition to Disease; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genomics; Haplotypes; Health aspects; HeLa Cells; Human Genetics; Humans; Leber Congenital Amaurosis - complications; Leber Congenital Amaurosis - genetics; Leber's congenital amaurosis; letter; Male; Medical research; Medical sciences; Middle Aged; Mutation; Mutation - physiology; Neurodegeneration; Nicotinamide-Nucleotide Adenylyltransferase - genetics; Nicotinamide-Nucleotide Adenylyltransferase - physiology; Ophthalmology; Pedigree; Proteins; Retinal degeneration; Retinal Degeneration - complications; Retinal Degeneration - genetics; Retinopathies; Signal Transduction - genetics; Studies; Young Adult; Canada; United Kingdom; United States; China; Macular degeneration; Eye disease; Leber amaurosis; Retinopathy; Congenital; Identification; Mutation; Genetic disease
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.2356

Rui Chen and colleagues identify mutations in NMNAT1 as a new cause of Leber congenital amaurosis. They further show that all examined individuals with NMNAT1 mutations have macular colobomas, a condition marked by severe degeneration of the central retina. 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 ( Wld s ) 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.