title: Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration.
abstract: 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.
authors: McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
authors: Robert K
authors: RK
authors: Koenekoop
authors: Hui
authors: H
authors: Wang
authors: Jacek
authors: J
authors: Majewski
authors: Xia
authors: X
authors: Wang
authors: Irma
authors: I
authors: Lopez
authors: Huanan
authors: H
authors: Ren
authors: Yiyun
authors: Y
authors: Chen
authors: Yumei
authors: Y
authors: Li
authors: Gerald A
authors: GA
authors: Fishman
authors: Mohammed
authors: M
authors: Genead
authors: Jeremy
authors: J
authors: Schwartzentruber
authors: Naimesh
authors: N
authors: Solanki
authors: Elias I
authors: EI
authors: Traboulsi
authors: Jingliang
authors: J
authors: Cheng
authors: Clare V
authors: CV
authors: Logan
authors: Martin
authors: M
authors: McKibbin
authors: Bruce E
authors: BE
authors: Hayward
authors: David A
authors: DA
authors: Parry
authors: Colin A
authors: CA
authors: Johnson
authors: Mohammed
authors: M
authors: Nageeb
authors: James A
authors: JA
authors: Poulter
authors: Moin D
authors: MD
authors: Mohamed
authors: Hussain
authors: H
authors: Jafri
authors: Yasmin
authors: Y
authors: Rashid
authors: Graham R
authors: GR
authors: Taylor
authors: Vafa
authors: V
authors: Keser
authors: Graeme
authors: G
authors: Mardon
authors: Huidan
authors: H
authors: Xu
authors: Chris F
authors: CF
authors: Inglehearn
authors: Qing
authors: Q
authors: Fu
authors: Carmel
authors: C
authors: Toomes
authors: Rui
authors: R
authors: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D015331:Cohort Studies; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics* / Q000502:physiology; D010375:Pedigree; D012162:Retinal Degeneration / Q000150:complications / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
chemical_list: C484007:NMNAT1 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase