IMPDH1 – Leber congenital amaurosis 11

IMPHD1 (IMPDH1) encodes inosine 5′-monophosphate dehydrogenase type I, a rate-limiting enzyme in guanine nucleotide biosynthesis. Pathogenic missense variants in IMPDH1 cause autosomal dominant retinitis pigmentosa 10 and have been implicated in Leber congenital amaurosis 11 (PMID:37569264).

Genetic screening of 203 adRP, 55 arRP, 7 isolated RP, 17 macular degeneration, and 24 LCA patients identified two heterozygous missense variants—Arg105Trp and Asn198Lys—in two unrelated probands with isolated Leber congenital amaurosis. These findings implicate IMPDH1 in LCA11 but lacked familial segregation data (PMID:16384941). No loss-of-function variants have been reported in LCA11 cohorts.

Inheritance is autosomal dominant, consistent with RP10. Segregation analysis has not been documented for LCA11-associated variants, and no additional affected relatives were reported.

The variant spectrum in IMPDH1-associated LCA11 is dominated by missense substitutions clustering in the CBS and allosteric domains. Functional analyses of analogous adRP variants, such as D226N and Asp311Asn, demonstrate impaired nucleic acid binding and disrupted filament assembly (PMID:15882147; PMID:18974094).

A recent case report of a 13-year-old heterozygous for the novel c.134A>G (p.Tyr45Cys) variant showed no signs of peripheral retinal dystrophy or LCA features, supporting likely benign status for this allele (PMID:37569264).

Mechanistic studies reveal that IMPDH1 missense mutations exert a dominant-negative effect by altering nucleic acid interactions and polyribosome association, perturbing photoreceptor GTP homeostasis. Animal model rescue by RNAi underscores the functional impact of mutant IMPDH1 in photoreceptor degeneration (PMID:18385099).

Overall, the gene–disease association for IMPDH1 and LCA11 is currently classified as Limited clinical validity due to sparse case descriptions, absence of segregation, and reliance on functional data. Further pedigrees and segregation analysis are required to achieve a definitive classification. Key take-home: IMPDH1 missense variants confer risk for LCA11 in an autosomal dominant manner, but variant interpretation demands rigorous case ascertainment and functional corroboration.

References

• International journal of molecular sciences • 2023 • Novel Variant IMPDH1 c.134A>G, p.(Tyr45Cys): Phenotype-Genotype Correlation Revealed Likely Benign Clinical Significance. PMID:37569264
• 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
• The Journal of biological chemistry • 2008 • IMP dehydrogenase type 1 associates with polyribosomes translating rhodopsin mRNA. PMID:18974094
• 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

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