Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration


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 (Wlds) 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.

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Figure 1: NMNAT1 variants identified in individuals with LCA.
Figure 2: Retinal phenotypes of six individuals with NMNAT1 mutations.
Figure 3: Functional assays of mutant NMNAT1 proteins.

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We thank all of the individuals with LCA and their parents who were involved in this study. We thank R. Sifers for scientific discussion and J.E. Zaneveld for critical reading of the manuscript. R.K.K. is supported by the Foundation Fighting Blindness Canada, the Canadian Institutes for Health Research, the US National Institutes of Health (NIH), Reseau Vision, the Fonds de la Recherche en Santé du Québec (FRSQ) and FORGE Canada. We acknowledge the FORGE Canada Consortium. We thank R. Pigeon for coordinating all the individuals with LCA. G.A.F. acknowledges the Pangere Corporation, Grousbeck Foundation and the Wynn-Gund Foundation for financial support. We sincerely acknowledge The Royal Society (C.T. is a university research fellow), Yorkshire Eye Research and The Sir Jules Thorn Charitable Trust (grant 09/JTA). Exome sequencing was performed at the BCM–Functional Genome Initiative (BCM-FGI) core facility, which is supported by NIH shared instrument grant 1S10RR026550 to R.C. H.W. was supported by postdoctoral fellowship F32EY19430. J.C. was supported by the Graduate Innovation Foundation of Hunan Province (CX2011B388). This work is supported by grants from the Retinal Research Foundation and the National Eye Institute (R01EY018571) to G.M. and R.C.

The FORGE Steering Committee comprises K. Boycott (leader; University of Ottawa, Ottawa, Ontario, Canada), J. Friedman (co-lead; University of British Columbia, Vancouver, British Columbia, Canada), J. Michaud (co-lead; Université de Montréal, Montreal, Quebec, Canada), F. Bernier (University of Calgary, Calgary, Alberta, Canada), M. Brudno (University of Toronto, Toronto, Ontario, Canada), B. Fernandez (Memorial University, St. John's, Newfoundland, Canada), B. Knoppers (McGill University, Montreal, Quebec, Canada), M. Samuels (Université de Montréal, Montreal, Quebec, Canada) and S. Scherer (University of Toronto, Toronto, Ontario, Canada). This work was funded in part by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research and the Ontario Genomics Institute (OGI-049). Additional funding was provided by Genome Quebec and Genome British Columbia. We thank J. Marcadier (Clinical Coordinator) and C. Beaulieu (Project Manager) for their contribution to the infrastructure of the FORGE Canada Consortium.

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R.K.K., C.F.I., C.T. and R.C. conceived the study. Y.C., Y.L. and H.X. performed the biochemistry and cell culture studies, H.W., I.L., H.R., N.S. and J.C. performed the sequencing, J.M., I.L., G.A.F., M.G., J.S., E.I.T., C.V.L., M.M., B.E.H., D.A.P., C.A.J., M.N., J.A.P., M.D.M., H.J., Y.R., G.R.T., V.K. and Q.F. carried out subject recruitment, and H.W. and I.L. performed pedigree analyses. R.K.K., H.W., J.M., X.W., C.F.I., C.T. and R.C. analyzed the data. R.K.K., H.W., X.W., G.M., C.F.I., C.T. and R.C. wrote and edited the manuscript.

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Correspondence to Rui Chen.

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The authors declare no competing financial interests.

Additional information

Members of the Steering Committee are given in the Acknowledgments.

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Supplementary Figures 1–4 and Supplementary Tables 1 and 2 (PDF 394 kb)

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Koenekoop, R., Wang, H., Majewski, J. et al. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nat Genet 44, 1035–1039 (2012).

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