IMPDH1 – Inherited Retinal Dystrophy

IMPDH1 (inosine 5'-monophosphate dehydrogenase 1) encodes a ubiquitously expressed enzyme essential for guanine nucleotide biosynthesis that exists as unique, photoreceptor-enriched splice variants in the retina ([PMID:16936083]). Heterozygous missense mutations in IMPDH1 cause autosomal dominant forms of inherited retinal dystrophy (including retinitis pigmentosa type 10 and rare Leber congenital amaurosis) by perturbing non–enzymatic functions despite preserved catalytic activity.

Multiple genetic studies have identified 23 unrelated probands with heterozygous IMPDH1 variants across diverse populations, including single nucleotide changes clustering in exons 8–10 and recurrent alleles c.931G>A (p.Asp311Asn) and c.940A>C (p.Lys314Gln), as well as in-frame and truncating changes absent from controls, segregating with disease in extended families ([PMID:32507954], [PMID:24791140], [PMID:16384941], [PMID:37259572], [PMID:38604988]). The variant spectrum comprises over 56 distinct alleles: 43 missense, 3 in-frame, 1 nonsense, 2 frameshift, 1 synonymous affecting splicing, and 6 intronic variants.

Inheritance is autosomal dominant with evidence of segregation in at least 19 affected relatives from multiple families harboring IMPDH1 mutations. Recurrent founder alleles have not been described, and population carrier frequencies remain low.

Functional work demonstrates that disease-linked mutations (e.g., p.Arg309Pro, p.Asp311Asn, p.Asp226Asn) do not alter catalytic activity but disrupt single-stranded nucleic acid binding, mislocalize between nucleus and cytoplasm, and impair assembly into regulatory filaments (cytoophidia), suggesting a dominant-negative mechanism ([PMID:15882147], [PMID:21791244], [PMID:37731818]). Cryo-EM and biochemical assays reveal that retina-specific terminal extensions modulate filament interfaces and GTP feedback sensitivity, and that pathogenic variants compromise these allosteric controls ([PMID:35013599], [PMID:38323936]). RNAi-mediated suppression of mutant IMPDH1 in murine retina rescues photoreceptor degeneration, underscoring therapeutic potential ([PMID:18385099]).

No robust conflicting evidence disputes the association between heterozygous IMPDH1 mutations and autosomal dominant retinal dystrophy. Additional studies on animal models and long-term natural history exceed current scoring limits.

Key Take-home: Dominant-negative IMPDH1 variants that impair nucleic acid binding and filament regulation lead to progressive inherited retinal dystrophy, providing a rationale for targeted gene-silencing therapies.

References

• International ophthalmology • 2020 • Morpho-functional survey in children suspected of inherited retinal dystrophies via video recording, electrophysiology and genetic analysis. PMID:32507954
• Molecular vision • 2014 • Detecting genetic variations in hereditary retinal dystrophies with next-generation sequencing technology. PMID:24791140
• Investigative ophthalmology & visual science • 2006 • Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis. PMID:16384941
• Ophthalmic genetics • 2023 • IMPDH1-associated autosomal dominant retinitis pigmentosa: natural history of novel variant Lys314Gln and a comprehensive literature search. PMID:37259572
• Current eye research • 2024 • Datasets-Based IMPDH1 Revisited: Heterozygous Missense Variants for Dominant Retinitis Pigmentosa While Truncation Variants Are Likely Non-Pathogenic. PMID:38604988
• The Biochemical journal • 2005 • Autosomal dominant retinitis pigmentosa mutations in inosine 5'-monophosphate dehydrogenase type I disrupt nucleic acid binding. PMID:15882147
• Biochimica et biophysica acta • 2011 • Molecular recruitment as a basis for negative dominant inheritance? propagation of misfolding in oligomers of IMPDH1, the mutated enzyme in the RP10 form of retinitis pigmentosa. PMID:21791244
• Frontiers in cell and developmental biology • 2023 • Effect on cell survival and cytoophidium assembly of the adRP-10-related IMPDH1 missense mutation Asp226Asn. PMID:37731818
• Nature structural & molecular biology • 2022 • IMPDH1 retinal variants control filament architecture to tune allosteric regulation. PMID:35013599
• The Journal of cell biology • 2024 • Light-sensitive phosphorylation regulates retinal IMPDH1 activity and filament assembly. PMID:38323936
• 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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