IMPDH1 – Retinitis Pigmentosa

Mutations in the IMPDH1 gene underlie a form of autosomal dominant Retinitis Pigmentosa (RP10), accounting for approximately 2% of adRP cases in European-origin cohorts (PMID:16384941). Pathogenic variants cluster within or downstream of the CBS domains (exons 8–10), with both recurrent and novel missense changes.

In a Swedish pedigree, the c.677G>A (p.Asp226Asn) variant segregated with disease in nine carriers across three generations, with eight additional affected relatives demonstrating rod-predominant degeneration, preserved central cone function, and foveal edema (PMID:16272056). This segregation firmly establishes autosomal dominant transmission.

A targeted screen of 203 adRP patients identified five distinct IMPDH1 variants—Thr116Met, Asp226Asn, Val268Ile, Gly324Asp, His372Pro—in eight unrelated families, confirming a ~2% prevalence of IMPDH1 mutations in adRP (PMID:16384941). Additional studies in diverse populations (French Canadian, Chinese) have repeatedly detected the recurrent c.931G>A (p.Asp311Asn) allele, underscoring its diagnostic relevance.

Biochemical assays reveal that adRP-linked IMPDH1 mutants do not impair enzymatic catalytic activity but uniformly disrupt single-stranded nucleic acid binding and alter subcellular distribution (PMID:15882147). Cryo-EM studies further show that retinal splice variants assemble polymorphic filaments whose regulation by GTP is perturbed by disease variants, providing an allosteric basis for photoreceptor specificity (PMID:35013599).

In vivo, adeno-associated virus (AAV)–mediated RNA interference targeting mutant IMPDH1 in a murine RP10 model markedly rescues photoreceptor survival without overt toxicity, demonstrating therapeutic proof-of-concept (PMID:18385099).

Collectively, autosomal dominant IMPDH1 mutations exhibit strong genetic and functional concordance with RP10. Clinical testing for IMPDH1 variants is recommended in adRP diagnostics, and RNAi-based strategies hold promise for mutation-specific therapy.

References

• Ophthalmic genetics • 2005 • Clinical phenotype in a Swedish family with a mutation in the IMPDH1 gene. PMID:16272056
• 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
• Human molecular genetics • 2008 • Therapeutic benefit derived from RNAi-mediated ablation of IMPDH1 transcripts in a murine model of autosomal dominant retinitis pigmentosa (RP10). PMID:18385099
• Nature structural & molecular biology • 2022 • IMPDH1 retinal variants control filament architecture to tune allosteric regulation. PMID:35013599

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