Curation OPDM2 GIPC1

GIPC1 5' UTR GGC repeat expansions were detected in 3/8 Chinese OPDM families and 9/16 sporadic Chinese OPDM cases, plus 7/194 unrelated Japanese OPDM cases; expansions were absent from 1,000 unaffected Chinese controls and were validated by LRS, RP-PCR, and AL-PCR.

In an independent Chinese OPDM cohort, GIPC1 5' UTR CGG expansion was identified in 4/7 families and 10/20 sporadic cases, co-segregated in Family 1 with linkage support (LOD 3.3), was absent from 376 control alleles, and showed a slight inverse correlation between repeat number and age at onset across 40 Chinese GIPC1-expanded OPDM patients (r = -0.398, P = 0.0163); controls had 6-29 repeats and pathogenic expansion was estimated >60 repeats.

Targeted long-read dmTGS screening of 57 patients with suspected genetic muscular disease confirmed a GIPC1 GGC repeat expansion in one patient; this is locus-specific clinical utility/proband evidence rather than a detailed OPDM2 case series.

In poly-G-expressing cell models of GIPC1 CGG repeat translation, HSPB1 overexpression disrupted SQSTM1-poly-G binding, reduced SQSTM1 sequestration in insoluble fractions, restored SQSTM1 puncta formation, and rescued starvation-induced autophagy activation impaired by poly-G aggregates.

Two unrelated GIPC1 CGG expansion carriers with OPDM-like myopathy and later parkinsonism (93 and 96 repeats) showed p62-positive intranuclear inclusions in skin biopsy; case 1 also showed p62-positive muscle-cell inclusions and filamentous intranuclear aggregates by EM.

Locus-specific but non-OPDM phenotype evidence: patient-derived skin fibroblasts from two GIPC1 CGG expansion-positive movement-disorder cases showed p62/ubiquitin-positive nuclear inclusions and downregulated GIPC1 mRNA and protein by qRT-PCR and western blot.