GIPC1 – Oculopharyngodistal Myopathy

Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disorder characterized by progressive ptosis [HP:0000508], external ophthalmoplegia [HP:0000544], distal muscle weakness [HP:0002460], and dysarthria [HP:0001260]. In 2020, comprehensive genomic analyses including whole-genome sequencing, long-read sequencing, and repeat-primed PCR identified GGC repeat expansions in the 5′ untranslated region of GIPC1 as the molecular cause in one of four Chinese families and in three sporadic individuals (PMID:32413282). Subsequent confirmation in a southwestern Chinese lineage (two affected) and in additional sporadic cases reinforced the association (PMID:35314910).

Overall, GIPC1 expansions have been detected in 23 independent probands (16 sporadic and 7 familial), with co-segregation observed across four unrelated pedigrees and multiple affected relatives (PMID:32413282; PMID:35314910). The pathogenic change comprises a noncoding GGC repeat expansion in the 5′ UTR of GIPC1 acting via an autosomal-dominant, gain-of-function RNA toxicity mechanism, although variable inheritance patterns have been reported.

Functional studies demonstrate hypermethylation of the expanded allele, elevated GIPC1 mRNA without corresponding protein increase, and dysregulation of p53 signaling, vascular smooth muscle contraction, ubiquitin-mediated proteolysis, and ribosome pathways in muscle tissue (PMID:32413282). Patient-derived induced pluripotent stem cells carrying the same expansion recapitulate pluripotency and three-germ-layer differentiation, validating a disease model (PMID:36055118).

The clinical spectrum may extend beyond myopathy: two unrelated OPDM2 patients developed parkinsonism with p62-positive intranuclear inclusions in skin, suggesting shared pathogenic pathways with other CGG repeat disorders (PMID:39418922).

Collectively, robust genetic and experimental concordance across independent cohorts and mechanistic studies support a Strong clinical validity classification for GIPC1 in OPDM (23 probands; familial segregation; concordant functional data). Testing for GIPC1 repeat expansions is recommended in adult-onset OPDM for diagnosis, management, and genetic counseling.

References

• American Journal of Human Genetics • 2020 • Expansion of GGC Repeat in GIPC1 Is Associated with Oculopharyngodistal Myopathy. PMID:32413282
• Neurological Sciences • 2022 • Oculopharyngodistal myopathy with CGG repeat expansions in GIPC1: the first report from southwestern China. PMID:35314910
• Stem Cell Research • 2022 • Human-induced pluripotent stem cell line (FDHSi001-A) derived from a patient with a CGG repeat expansion in the 5'UTR of GIPC1. PMID:36055118
• Neuromuscular Disorders • 2024 • Sequential development of parkinsonism in two patients with oculopharyngodistal type myopathy in GIPC1-related repeat expansion disorder. PMID:39418922

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