IMPDH1 – IMPDH1-associated Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a severe early-onset retinal dystrophy presenting with profound visual impairment in infancy. The IMPDH1 gene, encoding inosine monophosphate dehydrogenase 1, has been implicated in a rare autosomal dominant form of LCA. In a cohort of 24 unrelated LCA patients, two de novo missense variants (Arg105Trp, Asn198Lys) were identified, absent from controls, establishing a low‐frequency contribution to disease (PMID:16384941). No additional segregation was observed, and the overall prevalence of IMPDH1 mutations in LCA remains under 5%.

Functional and structural studies support a dominant‐negative or gain‐of‐function mechanism. Biochemical assays of adRP‐linked mutations R224P and D226N demonstrate preserved catalytic activity but markedly reduced single‐stranded nucleic acid binding, suggesting disruption of a noncanonical RNA‐binding role in photoreceptors (PMID:15882147). Cryo‐EM analyses reveal that retinal‐specific IMPDH1 splice variants assemble into filaments that modulate GTP feedback inhibition; pathogenic mutations alter filament architecture and allosteric regulation, consistent with photoreceptor degeneration pathways (PMID:35013599). Key take-home: Although rare, autosomal dominant IMPDH1 variants causally contribute to LCA via disrupted nucleotide homeostasis and filament assembly, supporting inclusion in genetic diagnostic panels.

References

• Investigative ophthalmology & visual science • 2006 • Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis. PMID:16384941
• The Biochemical journal • 2005 • Autosomal dominant retinitis pigmentosa mutations in inosine 5'-monophosphate dehydrogenase type I disrupt nucleic acid binding. PMID:15882147
• Nature structural & molecular biology • 2022 • IMPDH1 retinal variants control filament architecture to tune allosteric regulation. PMID:35013599

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