OPDM2_GIPC1
- Gene
- GIPC1
- Disease
- OPDM2
- Inheritance
- AD
- Classification
- Definitive
- Total Score
- 15.5
- Publications Reviewed
- 6
- Publication Span
- 4.99 years
- Last Updated
- 06/04/2025
- Curator(s)
- Laurel Hiatt, Harriet Dashnow
Description
Autosomal dominant OPDM2 is associated with heterozygous CGG/GGC repeat expansion in the 5' UTR of GIPC1. Across independent cohorts, expanded alleles were identified in familial and sporadic OPDM cases, were absent or very rare in controls, and showed repeat-size association with age at onset/pathogenic thresholds. Functional studies support a repeat-mediated mechanism involving altered GIPC1 expression, p62-positive intranuclear/rimmed-vacuole pathology, RAN translation of GIPC1 CGG repeats into poly-glycine proteins, autophagy-receptor sequestration, and rescue of poly-G-associated autophagy deficits by HSPB1 in cell models.
Genetic evidence
Total: 9.5
| Singular Evidence | Probands | PMID:32413282 | 6 | 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. |
| Collective Evidence | Allele | PMID:33374016 | 2 | 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. |
| Singular Evidence | Probands | PMID:39492694 | 1.5 | 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. |
Experimental evidence
Total: 6
| Rescue | Rescue in cell culture | PMID:39936620 | 2 | 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. |
| Functional Alteration | Patient cells | PMID:39418922 | 2 | 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. |
| Function | Regulatory impact | PMID:35152460 | 2 | 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. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.