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Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive photoreceptor degeneration leading to night blindness and visual field constriction. IMPG2 encodes interphotoreceptor matrix proteoglycan 2, a key extracellular matrix component essential for rod and cone cell integrity. Biallelic IMPG2 mutations have been implicated in autosomal recessive RP.
Genetic evidence supports an autosomal recessive inheritance. A pseudodominant pedigree (Family 4) demonstrated a compound heterozygous IMPG2 truncating allele c.2890C>T (p.Arg964Ter) segregating with RP in affected parents and offspring (PMID:33634125). In a cohort of 480 IRD patients, one RP case harbored compound heterozygous IMPG2 variants, confirming its role in human disease (PMID:39858590).
Segregation analysis revealed two additional affected relatives in the consanguineous family who were homozygous or compound heterozygous for loss-of-function IMPG2 variants, consistent with autosomal recessive transmission (PMID:33634125).
Functional assessment in two independent Impg2 knockout mouse models recapitulated RP phenotypes, including attenuated electroretinogram response and progressive degeneration of rod and cone photoreceptors by six months of age (PMID:32242237). Histopathology showed disorganized rod outer segments and rhodopsin mislocalization, with subsequent cone cell death.
Mechanistic studies revealed increased endoplasmic reticulum stress markers (CHOP, BIP, PDI) and impaired autophagy (SQSTM1 accumulation) in Impg2-KO retinas, supporting a loss-of-function pathogenic mechanism with disrupted photoreceptor homeostasis (PMID:32242237).
Together, the convergence of human genetic data—biallelic truncating variants, familial segregation—and in vivo functional concordance establishes a strong gene–disease association. IMPG2 mutation screening is recommended in AR RP diagnostic panels, aiding molecular diagnosis and carrier testing.
Key Take-home: Autosomal recessive loss-of-function variants in IMPG2 cause retinitis pigmentosa via photoreceptor degeneration driven by ER stress and autophagy defects.
Gene–Disease AssociationStrong2 RP probands with compound heterozygous IMPG2 loss-of-function variants, segregation in a pseudodominant family, and concordant KO mouse model Genetic EvidenceModerate2 probands with biallelic truncating variants and segregation in consanguineous pedigree Functional EvidenceModerateImpg2-KO mice show ERG attenuation, rod/cone degeneration, ER stress and autophagy impairment |