NMNAT1 mutations cause Leber congenital amaurosis

被引：156

作者：

Falk, Marni J. ^{[2
,4
]}

Zhang, Qi ^{[1
,5
]}

Nakamaru-Ogiso, Eiko ^{[3
]}

Kannabiran, Chitra ^{[6
]}

Fonseca-Kelly, Zoe ^{[1
,5
]}

Chakarova, Christina ^{[7
]}

Audo, Isabelle ^{[8
,9
,10
,11
]}

Mackay, Donna S. ^{[7
]}

Zeitz, Christina ^{[8
,9
,10
]}

Borman, Arundhati Dev ^{[7
,12
]}

Staniszewska, Magdalena ^{[1
,5
]}

Shukla, Rachna ^{[6
]}

Palavalli, Lakshmi ^{[6
]}

Mohand-Said, Saddek ^{[8
,9
,10
,11
]}

Waseem, Naushin H. ^{[7
]}

Jalali, Subhadra ^{[6
,13
]}

Perin, Juan C. ^{[14
]}

Place, Emily ^{[1
,2
,5
]}

Ostrovsky, Julian ^{[2
]}

Xiao, Rui ^{[15
]}

Bhattacharya, Shomi S. ^{[7
,16
]}

Consugar, Mark ^{[1
,5
]}

Webster, Andrew R. ^{[7
,12
]}

Sahel, Jose-Alain ^{[8
,9
,10
,11
,17
,18
]}

Moore, Anthony T. ^{[7
,12
,19
]}

Berson, Eliot L. ^{[1
]}

Liu, Qin ^{[1
,5
]}

Gai, Xiaowu ^{[20
,21
]}

Pierce, Eric A. ^{[1
,5
]}

机构：

[1] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat,Dept Opht, Boston, MA 02114 USA

[2] Childrens Hosp Philadelphia, Div Human Genet, Dept Pediat, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA

[4] Childrens Hosp Philadelphia, Dept Pediat, Div Child Dev & Metab Dis, Philadelphia, PA 19104 USA

[5] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Ocular Genom Inst, Boston, MA USA

[6] LVPEI, Kallam Anji Reddy Mol Genet Lab, Hyderabad, Andhra Pradesh, India

[7] UCL, Inst Ophthalmol, London, England

[8] INSERM, U968, Paris, France

[9] Univ Paris 06, Unite Mixte Rech UMR S 968, Inst Vis, Paris, France

[10] CNRS, UMR 7210, Paris, France

[11] Ctr Hosp Natl Ophtalmol Quinze Vingts, INSERM, DHOS, Ctr Invest Clin 503, Paris, France

[12] Moorfields Eye Hosp, London, England

[13] LVPEI, Srimati Kanuri Santhamma Ctr Vitreoretinal Dis, Hyderabad, Andhra Pradesh, India

[14] Childrens Hosp Philadelphia, Ctr Biomed Informat, Philadelphia, PA 19104 USA

[15] Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[16] Ctr Andaluz Biol Mol & Med Regenerat CABIMER, Seville, Spain

[17] Fdn Ophtalmol Adolphe Rothschild, Paris, France

[18] Acad Sci Inst France, Paris, France

[19] Great Ormond St Hosp Sick Children, London WC1N 3JH, England

[20] Loyola Univ, Chicago Hlth Sci Div, Dept Mol Pharmacol & Therapeut, Maywood, IL 60153 USA

[21] Loyola Univ, Chicago Hlth Sci Div, Ctr Biomed Informat, Maywood, IL 60153 USA

来源：

NATURE GENETICS | 2012年 / 44卷 / 09期

基金：

美国国家卫生研究院;

关键词：

GENE-THERAPY; WALLERIAN DEGENERATION; SUBCELLULAR COMPARTMENTATION; RETINITIS-PIGMENTOSA; PROTEIN; DISEASE; WLD(S); IDENTIFICATION; NICOTINAMIDE; DYSTROPHIES;

D O I：

10.1038/ng.2361

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1040 / +

页数：8

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