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Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis


Leber congenital amaurosis (LCA) is an autosomal recessive retinal dystrophy that manifests with genetic heterogeneity. We sequenced the exome of an individual with LCA and identified nonsense (c.507G>A, p.Trp169*) and missense (c.769G>A, p.Glu257Lys) mutations in NMNAT1, which encodes an enzyme in the nicotinamide adenine dinucleotide (NAD) biosynthesis pathway implicated in protection against axonal degeneration. We also found NMNAT1 mutations in ten other individuals with LCA, all of whom carry the p.Glu257Lys variant.

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We thank the subjects and their parents for participation in this study. The primary appointment of M.Q. is at the Zhejiang University School of Medicine. P.-W.C. and R.G.W. are grateful for the support of the Foundation Fighting Blindness (FFB). P.-W.C. is especially thankful to the parents of subject 1. Without their persistence and commitment, this work would not have been possible. This project was partially supported by a 985 Project Grant from the Ministry of Education of China (to M.Q.) and by the Qiangjiang Research Talent grant (2006R10018, to M.Q.) from the Science and Technology Department of Zhejiang Province. Q.F. and S.Y. are supported by funds from the Natural Science Foundation of Zhejiang Province (R2100439). Informed consent was obtained through the Casey Eye Institute Molecular Diagnostic Laboratory for the purpose of clinical testing and, subsequently, research testing if no mutations could be identified. This study was approved by the Oregon Health & Science University research integrity office (IRB00008083).

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P.-W.C. and M.Q. conceived the project and planned the experiments. J.S., M.D., D.W., C.B., E.H., L.A.R.G. and J.M.F.S. clinically characterized the LCA cases and collected blood samples. J.W., Yang Chen, J.Z., Yanhua Chen, X.Y., R.W., Yanling Chen and M.Q. performed next-generation sequencing experiments. H.G. and Y.S. performed validation experiments. P.-W.C. analyzed and interpreted the data. R.G.W. interpreted the clinical data. Q.F. and S.Y. analyzed and interpreted the structural data. P.C. and K.C. built the public LOVD database for the NMNAT1 gene and curated the clinical and mutation data. All authors contributed to the final manuscript.

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Correspondence to Ming Qi.

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Chiang, PW., Wang, J., Chen, Y. et al. Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis. Nat Genet 44, 972–974 (2012).

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