Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy

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In addition to its activity in nicotinamide adenine dinucleotide (NAD+) synthesis, the nuclear nicotinamide mononucleotide adenyltransferase NMNAT1 acts as a chaperone that protects against neuronal activity–induced degeneration. Here we report that compound heterozygous and homozygous NMNAT1 mutations cause severe neonatal neurodegeneration of the central retina and early-onset optic atrophy in 22 unrelated individuals. Their clinical presentation is consistent with Leber congenital amaurosis and suggests that the mutations affect neuroprotection of photoreceptor cells.

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Figure 1: NMNAT1 variants identified in individuals with LCA and funduscopic evidence of early-onset and fast-progressing macular atrophy.

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We are grateful to the individuals with Leber congenital amaurosis and their families for their participation in this study. We thank P. Debruyne for making available the fundus pictures of subject P4. This research was supported by the Association Retina France (grant to J.-M.R.) and the Assistance Publique–Hôpitaux de Paris (AP-HP; grant PHRC National-2009 AOM 09058/P081257 to J.K.). We also thank the Association Retina France for supporting the 100 Exomes project of the French Research Network aiming to speed the genetic analysis of inherited retinal diseases through whole-exome resequencing. Written consent was obtained from participants or legally authorized representatives. The study was conducted in strict adherence to the tenets of the Declaration of Helsinki and was approved by the Comité de Protection des Personnes Ile-de-France II.

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J.-M.R., J.K., H.D. and A.M. designed the study. I.P., S.H. and P.N. analyzed data from exome sequencing. I.P. and S.H. performed and analyzed data from Sanger sequencing of affected individuals and controls. M.N., N.D., L.F.-T. and S.G. performed linkage analyses at the LCA loci and Sanger sequencing of candidates to select the subjects to be screened for NMNAT1 mutations. O.X. performed and analyzed the LD analyses at the NMNAT1 locus. V.S. performed the three-dimensional structural analysis of NMNAT1 missense variants. J.K., H.D., X.Z., S.D.-D., C.E., A.G., A.D., G.L.M., C.H., E.S., P.C. and O.R. provided and analyzed clinical material from subjects. All authors contributed to the manuscript written by J.-M.R. and J.K.

Correspondence to Josseline Kaplan or Jean-Michel Rozet.

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