NMNAT1 – Leber congenital amaurosis 9

NMNAT1 encodes the nuclear nicotinamide mononucleotide adenylyltransferase 1, a rate-limiting enzyme in NAD+ biosynthesis with additional chaperone functions in photoreceptor survival. Biallelic loss-of-function and missense variants in NMNAT1 underlie Leber congenital amaurosis 9 (LCA9), a severe autosomal recessive retinal dystrophy presenting in infancy with profound visual impairment, nystagmus, nyctalopia and early macular/optic atrophy [PMID:22842229]. The enzyme’s ubiquitous expression contrasts with the retina-restricted phenotype, suggesting heightened photoreceptor NAD+ demand.

Inheritance is autosomal recessive with compound heterozygous or homozygous variants identified in over 30 unrelated individuals across >12 families ([PMID:22842229], [PMID:22842227]). Segregation analysis in consanguineous and non-consanguineous pedigrees confirms co-segregation of biallelic NMNAT1 variants with disease, with no unaffected homozygotes reported under high-coverage sequencing. A recent Iranian case reports compound heterozygosity for c.245T>C (p.Val82Ala) and c.575A>G (p.Asp192Gly) in a patient presenting with severe visual acuity reduction, nystagmus, night blindness and retinal degeneration, inherited from unaffected parents ([PMID:39445201]).

The variant spectrum includes missense substitutions, nonsense and frameshift alleles (e.g., c.648G>A (p.Trp216Ter)), canonical splice-site mutations, deep intronic changes, UTR variants (c.-70A>T) and structural rearrangements such as partial exon duplications, collectively defining a broad mutational landscape. Recurrent alleles include c.769G>A (p.Glu257Lys), which constitutes ~70% of LCA9 alleles but exhibits reduced penetrance in homozygotes [PMID:29674119, PMID:24830548]. No founder effect has been definitively established beyond population enrichment in European cohorts.

In vitro functional assessments demonstrate that many LCA9-associated missense variants maintain baseline NAD+ synthetic activity but display reduced thermal stability and increased unfolding under heat shock, implicating compromised protein folding and stress resilience as a pathogenic mechanism [PMID:26018082]. Enzyme assays of p.Val9Met reveal significantly reduced catalytic activity, supporting loss of function as the primary driver [PMID:22842227].

Murine models carrying the p.Val9Met or p.Asp243Gly knock-in alleles recapitulate key features of human LCA9, including progressive photoreceptor degeneration, vascular attenuation and optic atrophy by 3–6 months of age, validating pathogenicity in vivo ([PMID:27207593]). Conditional retina-specific knockout of Nmnat1 induces photoreceptor loss prior to terminal differentiation, underscoring its role in development and maintenance.

Gene augmentation via subretinal AAV delivery of human NMNAT1 in a p.Val9Met mouse model preserves retinal structure and function when administered within a narrow therapeutic window, providing the first proof-of-concept for targeted therapy in NMNAT1-associated retinal degeneration [PMID:32775493].

Although c.769G>A (p.Glu257Lys) acts as a hypomorphic allele with incomplete penetrance, compound heterozygosity with a null allele consistently produces the full LCA9 phenotype, indicating allele-specific effects on disease severity. Clinical non-penetrance of homozygous p.Glu257Lys necessitates cautious variant interpretation in genetic counseling [PMID:24830548].

Collectively, the wealth of genetic, segregation and functional data meets ClinGen criteria for a Definitive gene–disease association. NMNAT1 testing is clinically actionable for early molecular diagnosis, personalized counseling and emerging gene therapy trials. Key Take-home: NMNAT1 mutations cause a definitive autosomal recessive LCA9 through loss of enzymatic stability and function, with gene therapy offering a promising intervention.

References

• Clinical case reports • 2024 • Identification and characterization of NMNAT1 gene mutations in an Iranian patient with Leber congenital amaurosis 9. PMID:39445201
• 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:22842227
• Experimental eye research • 2018 • NMNAT1 E257K variant, associated with Leber Congenital Amaurosis (LCA9), causes a mild retinal degeneration phenotype. PMID:29674119
• JAMA ophthalmology • 2014 • Nonpenetrance of the most frequent autosomal recessive leber congenital amaurosis mutation in NMNAT1. PMID:24830548
• The Journal of biological chemistry • 2015 • Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants. PMID:26018082
• 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

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