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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
den Hollander, A.I. et al. Prog. Retin. Eye Res. 27, 391–419 (2008).
Sergouniotis, P.I. et al. Am. J. Hum. Genet. 89, 183–190 (2011).
Estrada-Cuzcano, A. et al. Invest. Ophthalmol. Vis. Sci. 52, 834–839 (2011).
Zhou, T. et al. J. Biol. Chem. 277, 13148–13154 (2002).
Perrault, I. et al. Hum. Mutat. 28, 416 (2007).
Raffaelli, N. et al. Biochem. Biophys. Res. Commun. 297, 835–840 (2002).
Berger, F. et al. J. Biol. Chem. 280, 36334–36341 (2005).
Conforti, L. et al. FEBS J. 278, 2666–2679 (2011).
Zhai, R.G. et al. PLoS Biol. 4, e416 (2006).
Mack, T.G. et al. Nat. Neurosci. 4, 1199–1206 (2001).
Coleman, M.P. et al. Annu. Rev. Neurosci. 33, 245–267 (2010).
Avery, M.A. et al. J. Cell Biol. 184, 501–513 (2009).
Feng, Y. et al. Protein Cell 1, 237–245 (2010).
Sasaki, Y. et al. J. Neurosci. 29, 5525–5535 (2009).
Lau, C. et al. J. Biol. Chem. 285, 18868–18876 (2010).
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.
The authors declare no competing financial interests.
About this article
Severe biallelic loss-of-function mutations in nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) in two fetuses with fetal akinesia deformation sequence
Experimental Neurology (2019)
Nutritional Neuroscience (2019)
Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1 -related fundus phenotype
Clinical Genetics (2018)
Ageing Research Reviews (2018)