NMNAT1 mutations cause Leber congenital amaurosis Journal Article

Authors: Falk, M. J.; Zhang, Q.; Nakamaru-Ogiso, E.; Kannabiran, C.; Fonseca-Kelly, Z.; Chakarova, C.; Audo, I.; Mackay, D. S.; Zeitz, C.; Borman, A. D.; Staniszewska, M.; Shukla, R.; Palavalli, L.; Mohand-Said, S.; Waseem, N. H.; Jalali, S.; Perin, J. C.; Place, E.; Ostrovsky, J.; Xiao, R.; Bhattacharya, S. S.; Consugar, M.; Webster, A. R.; Sahel, J. A.; Moore, A. T.; Berson, E. L.; Liu, Q.; Gai, X.; Pierce, E. A.
Article Title: NMNAT1 mutations cause Leber congenital amaurosis
Abstract: Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss(1,2). Two-thirds of LCA cases are caused by mutations in 17 known disease-associated genes(3) (Retinal Information Network (RetNet)). Using exome sequencing we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 that is likely to be disease causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in the kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD(+)) biosynthesis(4,5). Functional studies showed that the p.Val9Met alteration decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated families with LCA identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease in humans and indicate that NMNAT1 mutations cause LCA.
Journal Title: Nature genetics
Volume: 44
Issue: 9
ISSN: 1546-1718; 1061-4036
Publisher: Unknown  
Journal Place: United States
Date Published: 2012
Start Page: 1040
End Page: 1045
Language: eng
Notes: LR: 20130712; GR: P30EY014104/EY/NEI NIH HHS/United States; GR: P30HD026979/HD/NICHD NIH HHS/United States; GR: R01 EY012910/EY/NEI NIH HHS/United States; GR: R01 HD065858/HD/NICHD NIH HHS/United States; GR: R01-EY12910/EY/NEI NIH HHS/United States; GR: R01-GM097409/GM/NIGMS NIH HHS/United States; GR: R03 DK082521/DK/NIDDK NIH HHS/United States; GR: R03-DK082446/DK/NIDDK NIH HHS/United States; GR: UL1-RR-024134/RR/NCRR NIH HHS/United States; JID: 9216904; EC (NMNAT1 protein, human); EC (Nicotinamide-Nucleotide Adenylyltransferase); CIN: Clin Genet. 2013 Jan;83(1):33-4. PMID: 23088368; NIHMS390378; OID: NLM: NIHMS390378; OID: NLM: PMC3454532; 2012/02/12 [received]; 2012/06/29 [accepted]; 2012/07/29 [aheadofprint]; ppublish