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

Abstract

<p class="first" id="P1"> <i>NMNAT1</i> (nicotinamide mononucleotide adenylyltransferase 1) encodes a rate-limiting enzyme that catalyzes the biosynthesis of NAD ⁺ and plays a role in neuroprotection. Mutations in <i>NMNAT1</i> have been identified to cause a recessive, non-syndromic early form of blindness genetically defined as Leber Congenital Amaurosis 9 ( <i>LCA9)</i>. One of the most common alleles reported so far in <i>NMNAT1</i> is the c.769G&gt;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 <i>Nmnat1</i> 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 <i>Nmnat1 ^E257K/ </i> ⁻ mice exhibited photoreceptor defects which were exacerbated upon exposure to light. Furthermore, retina specific <i>Nmnat1</i> conditional knockout mice exhibit photoreceptor degeneration before the retina has terminally differentiated. These findings suggest that <i>NMNAT1</i> plays an important role in photoreceptors and is likely involved in both retinal development and maintenance of photoreceptor integrity. </p>