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

Nature Genetics volume 44, pages 972–974 (2012)Cite this article

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Abstract

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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Acknowledgements

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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Author notes

  1. Pei-Wen Chiang and Juan Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Casey Eye Institute Molecular Diagnostic Laboratory, Portland, Oregon, USA

    Pei-Wen Chiang, Haixue Gan & Yong Shi

  2. Beijing Genomics Institute (BGI)-Shenzhen, Shenzhen, China

    Juan Wang, Yang Chen, Jing Zhong, Yanhua Chen, Xin Yi, Renhua Wu & Ming Qi

  3. Center for Structural Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China

    Quan Fu & Sheng Ye

  4. Center for Genetic and Genomic Medicine, Zhejiang University School of Medicine First Affiliated Hospital and James D. Watson Institute of Genome Sciences, Hangzhou, China

    Yanling Chen, Peikuan Cong & Ming Qi

  5. SA Clinical Genetics Service, Women's and Children's Hospital, North Adelaide, South Australia, Australia

    Christopher Barnett

  6. Retina Foundation of the Southwest, Dallas, Texas, USA

    Dianna Wheaton

  7. Department of Ophthalmology, SickKids Hospital, Toronto, Ontario, Canada

    Megan Day, Joanne Sutherland & Elise Heon

  8. Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA

    Richard G Weleber

  9. Department of Ocular Genetics, Centro de Referência em Oftalmologia (CEROF), Federal University of Goias, Goiania, Brazil

    Luis Alexandre Rassi Gabriel

  10. Department of Pathology, University of Rochester Medical Center, Rochester, New York, USA

    KuangHsiang Chuang & Ming Qi

  11. Department of Ophthalmology, Federal University of Sao Paulo, Sao Paulo, Brazil

    Juliana Maria Ferraz Sallum

Authors
  1. Pei-Wen Chiang
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  2. Juan Wang
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  7. Xin Yi
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  8. Renhua Wu
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  9. Haixue Gan
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  10. Yong Shi
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  11. Yanling Chen
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  12. Christopher Barnett
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  13. Dianna Wheaton
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  14. Megan Day
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  16. Elise Heon
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  17. Richard G Weleber
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  19. Peikuan Cong
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  21. Sheng Ye
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  22. Juliana Maria Ferraz Sallum
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  23. Ming Qi
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Contributions

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.

Corresponding author

Correspondence to Ming Qi.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary Note, Supplementary Methods, Supplementary Tables 1–4 and Supplementary Figures 1–3 (PDF 688 kb)

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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). https://doi.org/10.1038/ng.2370

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