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31-07-2012 | Neurology | Article

Gene discovery made for infant-onset blindness


Free abstract

MedWire News: Researchers have discovered that mutations in the NMNAT1 gene encoding nicotinamide mononucleotide adenylyltransferase 1 are present in patients with Leber congenital amaurosis (LCA).

The finding could help explain the 30% of unresolved cases of LCA that do not display any of the 16 genes known to be associated with the blinding retinal disease that presents within the first year after birth, says the team.

Writing in Nature Genetics, Rui Chen (Baylor College of Medicine, Houston, Texas, USA) and colleagues explain that the molecular mechanisms underlying neurodegeneration are highly complex, and that strategies to prevent the process are under intense investigation.

"Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous disorder," they report.

The team sequenced and evaluated whole-exomes of 50 individuals with LCA without mutations in known LCA-causing genes and their next-generation relatives, and found three unrelated individuals with LCA with compound heterozygous variants in NMNAT1.

The absence of these mutations in 200 healthy individuals acting as controls "indicates that NMNAT1 is likely to be a new LCA-causing gene," say Chen et al, who sequenced a further 150 individuals with LCA and found four carried either compound heterozygous or homozygous mutations in this gene.

"In total, we identified ten mutant alleles of NMNAT1 in eight families with LCA," they report.

After re-examination of the phenotypes of the individuals with NMNAT1 mutations and interviews with them and their parents, the researchers found that those with biallelic mutations had macular coloboma - an indication of complete loss of neural tissue in the fovea. This associates NMNAT1 mutations with severe and rapid foveal degeneration, writes the team.

In a separate study also published in Nature Genetics, Josseline Kaplan (Université Paris Descartes-Sorbonne Paris Cité, France) and co-workers sequenced 256 individuals with LCA but no known LCA-causing genes, and found and confirmed 20 unrelated cases carrying NMNAT1 mutations.

They suggest that retinal delivery of exogenous NAD (nicotinamide adenine dinucleotide - in which NMNAT1 is an essential enzyme for biosynthesis) may not be sufficient to prevent the degeneration of photoreceptors in individuals with LCA who carry NMNAT1 mutations.

"Gene replacement therapy could be a preferable option," they conclude, while Chen and co-authors suggest that increasing NAD levels in LCA patients with NMNAT1 mutations could be a potential therapeutic option.

MedWire ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2012

By Sarah Guy, MedWire Reporter

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