IMPG1 – Retinitis Pigmentosa

Inherited retinal disorder retinitis pigmentosa (RP) is clinically and genetically heterogeneous. Exome sequencing in a family with autosomal dominant RP identified a canonical splice variant in IMPG1, c.1824+1G>A (PMID:32817297). The same splice change was detected in two additional families, and retrospective screening of 596 RP and VMD cases revealed eight further families with distinct missense or nonsense IMPG1 variants, totaling 11 unrelated probands ([PMID:32817297]).

The variant spectrum comprises a single splice-site variant c.1824+1G>A and multiple missense (e.g., p.Ser320Arg, p.Leu579Pro, p.Leu613Pro, p.Leu626Phe) and nonsense alleles, observed both monoallelically (autosomal dominant) and biallelically (autosomal recessive) ([PMID:32817297]). Segregation analysis confirmed co-segregation of IMPG1 variants with RP in three multiplex families ([PMID:32817297]).

Functional assays support a loss-of-function mechanism: morpholino-mediated knockdown of impg1 in medaka fish resulted in shortened rod and cone outer segments mirroring human RP ([PMID:32817297]). An Impg1–/– mouse model developed progressive photoreceptor degeneration, interphotoreceptor matrix disruption, and decreased 11-cis-retinal levels, consistent with clinical RP features ([PMID:36140676]).

Together, genetic and experimental data establish haploinsufficiency and loss-of-function as key pathogenic mechanisms for IMPG1-associated RP, reinforcing its diagnostic and therapeutic relevance.

References

• Journal of medical genetics • 2021 • Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa. PMID:32817297
• Genes • 2022 • SPACR Encoded by IMPG1 Is Essential for Photoreceptor Survival by Interplaying between the Interphotoreceptor Matrix and the Retinal Pigment Epithelium. PMID:36140676

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