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

Nature Genetics volume 44, pages 975–977 (2012)Cite this article

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Abstract

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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NCBI Reference Sequence

Protein Data Bank

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Acknowledgements

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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  1. Isabelle Perrault and Sylvain Hanein: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, Institut National de la Santé et de la Recherche Médicale (INSERM) U781, Université Paris Descartes–Sorbonne Paris Cité, Imagine Institute, Paris, France

    Isabelle Perrault, Sylvain Hanein, Valérie Serre, Michael Nicouleau, Nathalie Delphin, Lucas Fares-Taie, Sylvie Gerber, Olivia Xerri, Arnold Munnich, Josseline Kaplan & Jean-Michel Rozet

  2. Department of Vision Functional Exploration, Clinique Sourdille, Nantes, France

    Xavier Zanlonghi

  3. Department of Exploration of Vision and Neuro-Ophthalmology, Hôpital Roger Salengro, Centre Hospitalier Universitaire Régional, Lille, France

    Sabine Defoort-Delhemmes

  4. Department of Ophthalmology, Fondation Ophtalmologique Adolphe de Rothschild, Paris, France

    Catherine Edelson

  5. Department of Genetics, Centre Hospitalier Universitaire, Rouen, France

    Alice Goldenberg & Alice Duncombe

  6. Department of Ophthalmology, Centre Hospitalier Universitaire, Nantes, France

    Gylène Le Meur

  7. Neurosciences Institute, Hôpital Saint Eloi, Montpellier, France

    Christian Hamel

  8. Department of Ophthalmology, Coimbra University Hospital, Coimbra, Portugal

    Eduardo Silva

  9. Bioinformatics Platform, Université Paris Descartes–Sorbonne Paris Cité, Paris, France

    Patrick Nitschke

  10. Department of Medical Genetics, Purpan Hospital, Centre Hospitalier Universitaire, Toulouse, France

    Patrick Calvas

  11. Department of Ophthalmology, Université Paris Descartes–Sorbonne Paris Cité, Paris, France

    Olivier Roche

  12. Department of Clinical Genetics, Strasbourg University Hospital, Strasbourg, France

    Hélène Dollfus

Authors
  1. Isabelle Perrault
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  2. Sylvain Hanein
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  4. Valérie Serre
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  8. Lucas Fares-Taie
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  9. Sylvie Gerber
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  10. Olivia Xerri
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  11. Catherine Edelson
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  12. Alice Goldenberg
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  13. Alice Duncombe
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  16. Eduardo Silva
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  17. Patrick Nitschke
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  18. Patrick Calvas
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  19. Arnold Munnich
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  20. Olivier Roche
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  21. Hélène Dollfus
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  22. Josseline Kaplan
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  23. Jean-Michel Rozet
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Contributions

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.

Corresponding authors

Correspondence to Josseline Kaplan or Jean-Michel Rozet.

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The authors declare no competing financial interests.

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Perrault, I., Hanein, S., Zanlonghi, X. et al. Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy. Nat Genet 44, 975–977 (2012). https://doi.org/10.1038/ng.2357

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