NMNAT1 E257K variant, associated with Leber Congenital Amaurosis (LCA9), causes a mild retinal degeneration phenotype.

TitleNMNAT1 E257K variant, associated with Leber Congenital Amaurosis (LCA9), causes a mild retinal degeneration phenotype.
Publication TypeJournal Article
Year of Publication2018
AuthorsEblimit, A, Zaneveld, SAgrawal, Liu, W, Thomas, K, Wang, K, Li, Y, Mardon, G, Chen, R
JournalExp Eye Res
Date Published2018 Aug
KeywordsAlleles, Animals, Electroretinography, Exons, Female, Gene Knock-In Techniques, Genetic Variation, Leber Congenital Amaurosis, Light, Male, Mice, Mice, Knockout, Mice, Mutant Strains, Nicotinamide-Nucleotide Adenylyltransferase, Phenotype, Point Mutation, Radiation Injuries, Experimental, Retina, Retinal Degeneration

NMNAT1 (nicotinamide mononucleotide adenylyltransferase 1) encodes a rate-limiting enzyme that catalyzes the biosynthesis of NAD and plays a role in neuroprotection. Mutations in NMNAT1 have been identified to cause a recessive, non-syndromic early form of blindness genetically defined as Leber Congenital Amaurosis 9 (LCA9). One of the most common alleles reported so far in NMNAT1 is the c.769G > A (E257K) missense mutation, which occurs in 70% of all LCA9 cases. However, given its relatively high population frequency and the observation of individuals with homozygous E257K variant without phenotype, the pathogenicity of this allele has been questioned. To address this issue, we have studied the pathogenic effects of this allele by generating a knock-in mouse model. Interestingly, no obvious morphological or functional defects are observed in Nmnat1 E257K homozygous mice up to one year old, even after light-damage. Together with the previous clinical reports, we propose that the E257K allele is a weak hypomorphic allele that has significantly reduced penetrance in the homozygous state. In contrast, compound heterozygous Nmnat1 mice exhibit photoreceptor defects which are exacerbated upon exposure to light. Furthermore, retina tissue- specific Nmnat1 conditional knockout mice exhibit photoreceptor degeneration before the retina has terminally differentiated. These findings suggest that NMNAT1 plays an important role in photoreceptors and is likely involved in both retinal development and maintenance of photoreceptor integrity.

Alternate JournalExp Eye Res
PubMed ID29674119
PubMed Central IDPMC6054811
Grant ListR01 EY020540 / EY / NEI NIH HHS / United States
P30 HD024064 / HD / NICHD NIH HHS / United States
R01 EY022356 / EY / NEI NIH HHS / United States
P30 EY002520 / EY / NEI NIH HHS / United States
R01 EY018571 / EY / NEI NIH HHS / United States
T32 EY007102 / EY / NEI NIH HHS / United States

Similar Publications