NMNAT1 – Leber congenital amaurosis

Leber congenital amaurosis (LCA) is a severe autosomal recessive retinal dystrophy presenting in infancy with profound vision loss and characteristic fundus changes. Biallelic variants in NMNAT1 (HGNC:17877), encoding nuclear nicotinamide mononucleotide adenylyltransferase 1, underlie LCA9 ([PMID:22842227]). Initial exome sequencing in a consanguineous kindred identified a homozygous c.25G>A (p.Val9Met) substitution segregating with disease in five affected siblings and absent in unaffected relatives ([PMID:22842227]).

Genetic studies encompassing 284 unrelated families revealed 14 rare NMNAT1 mutations in 13 additional probands, including nonsense, missense, frameshift, and splice variants, confirming autosomal recessive inheritance ([PMID:22842231]). Segregation analyses demonstrated co-segregation of biallelic variants in multiple kindreds and compound heterozygotes across diverse populations, supporting pathogenicity. Deep-intronic 5′UTR substitutions (c.-70A>T, c.-69C>T) and copy-number variations further expand the mutational spectrum ([PMID:26316326]).

The variant spectrum includes at least 35 probands with missense (e.g., p.Val9Met), nonsense (e.g., p.Trp169Ter), frameshift (e.g., p.Glu131fs), and splicing defects, plus regulatory and structural alleles ([PMID:22842227]; [PMID:26316326]). No founder mutations have been conclusively established, though p.Glu257Lys occurs at elevated heterozygous frequency in Europeans. Carrier frequencies approximate 0.5% in certain cohorts.

Mechanistic studies demonstrate that LCA-associated NMNAT1 mutants reduce NAD+ synthesizing activity, destabilize protein folding under stress, and impair chaperone-mediated neuroprotection ([PMID:22842230]; [PMID:26018082]). Knock-in and knockout mouse models recapitulate early-onset photoreceptor degeneration, optic atrophy, and fundus scarring, confirming a loss-of-function mechanism ([PMID:27207593]; [PMID:33709122]). Gene augmentation using AAV-delivered human NMNAT1 rescues retinal structure and function in mutant mice, illustrating therapeutic potential ([PMID:32775493]).

Conflicting evidence arises from the nonpenetrance of the p.Glu257Lys allele: homozygotes exhibit no ocular phenotype at expected frequencies 80-fold lower than predicted, indicating variable expressivity or incomplete penetrance ([PMID:24830548]).

Together, genetic and functional data establish a Definitive association between NMNAT1 and Leber congenital amaurosis. Further studies on variant-specific penetrance and genotype–phenotype correlations will refine diagnosis and guide gene therapy timing. Key take-home: Early genetic testing for NMNAT1 variants enables prompt diagnosis, informs prognosis, and supports emerging AAV-based interventions.

References

• Nature genetics • 2012 • NMNAT1 mutations cause Leber congenital amaurosis PMID:22842227
• Nature genetics • 2012 • Exome sequencing identifies NMNAT1 mutations as a cause of Leber congenital amaurosis PMID:22842231
• Nature genetics • 2012 • Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy PMID:22842229
• Nature genetics • 2012 • Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration PMID:22842230
• JAMA ophthalmology • 2014 • Nonpenetrance of the most frequent autosomal recessive leber congenital amaurosis mutation in NMNAT1 PMID:24830548
• The American journal of pathology • 2016 • Mouse Models of NMNAT1-Leber Congenital Amaurosis (LCA9) Recapitulate Key Features of the Human Disease PMID:27207593
• Molecular therapy. Methods & clinical development • 2020 • Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal Degeneration PMID:32775493
• Human mutation • 2015 • Hidden Genetic Variation in LCA9-Associated Congenital Blindness Explained by 5′UTR Mutations and Copy-Number Variations of NMNAT1 PMID:26316326

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