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.
authors: Department of Pediatrics, Division of Human Genetics, The Children's Hospital of Philadelphia, Pennsylvania, USA.
authors: Marni J
authors: MJ
authors: Falk
authors: Qi
authors: Q
authors: Zhang
authors: Eiko
authors: E
authors: Nakamaru-Ogiso
authors: Chitra
authors: C
authors: Kannabiran
authors: Zoe
authors: Z
authors: Fonseca-Kelly
authors: Christina
authors: C
authors: Chakarova
authors: Isabelle
authors: I
authors: Audo
authors: Donna S
authors: DS
authors: Mackay
authors: Christina
authors: C
authors: Zeitz
authors: Arundhati Dev
authors: AD
authors: Borman
authors: Magdalena
authors: M
authors: Staniszewska
authors: Rachna
authors: R
authors: Shukla
authors: Lakshmi
authors: L
authors: Palavalli
authors: Saddek
authors: S
authors: Mohand-Said
authors: Naushin H
authors: NH
authors: Waseem
authors: Subhadra
authors: S
authors: Jalali
authors: Juan C
authors: JC
authors: Perin
authors: Emily
authors: E
authors: Place
authors: Julian
authors: J
authors: Ostrovsky
authors: Rui
authors: R
authors: Xiao
authors: Shomi S
authors: SS
authors: Bhattacharya
authors: Mark
authors: M
authors: Consugar
authors: Andrew R
authors: AR
authors: Webster
authors: José-Alain
authors: JA
authors: Sahel
authors: Anthony T
authors: AT
authors: Moore
authors: Eliot L
authors: EL
authors: Berson
authors: Qin
authors: Q
authors: Liu
authors: Xiaowu
authors: X
authors: Gai
authors: Eric A
authors: EA
authors: Pierce
mesh_terms: D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000150:complications / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000502:physiology; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics* / Q000502:physiology; D010375:Pedigree; D012162:Retinal Degeneration / Q000150:complications / Q000175:diagnosis / Q000235:genetics
chemical_list: C484007:NMNAT1 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase