COMP – Multiple Epiphyseal Dysplasia Type 1

COMP encodes cartilage oligomeric matrix protein, a pentameric extracellular matrix glycoprotein critical for cartilage integrity. Heterozygous COMP variants cause multiple epiphyseal dysplasia type 1 (MED1), an autosomal dominant skeletal dysplasia characterized by delayed epiphyseal ossification, joint pain, waddling gait, and mild short stature.

Clinical Validity

The COMP–MED1 association is classified as Moderate: three unrelated MED1 probands with heterozygous COMP variants have been reported (two in a cohort study ([PMID:34709441]), one in a targeted NGS panel ([PMID:30541462])). Experimental data across multiple models consistently support the pathogenicity of MED1‐associated COMP mutations.

Genetic Evidence

Inheritance is Autosomal dominant. To date, three unrelated MED1 probands have been described ([PMID:34709441]; [PMID:30541462]). No additional familial segregation data are available. Reported MED1‐associated COMP variants include c.1081G>T (p.Asp361Tyr) ([PMID:11084047]).

Functional Evidence

MED1‐associated mutations within the calcium‐binding type 3 repeats (e.g., p.Asp361Tyr) reduce calcium binding and alter COMP conformation ([PMID:10852928]; [PMID:11084047]), impair secretion with rER retention and ER stress (e.g., p.Asp472Tyr) ([PMID:12819015]), and disrupt collagen interactions. These concordant in vitro and cell‐based assays recapitulate cartilage defects, demonstrating a dominant‐negative mechanism.

Integrated Conclusion

Heterozygous COMP mutations in type 3 repeats underlie MED1 via dominant‐negative misfolding, ER retention, impaired calcium and collagen binding, and chondrocyte dysfunction. While genetic evidence is limited by proband numbers, robust functional concordance establishes clinical validity. Additional segregation data would further solidify this association.

Key Take-home: COMP mutational analysis should be included in diagnostic panels for autosomal dominant MED1 to guide clinical management and genetic counseling.

References

• Genotype and phenotype analysis of COMP variants in PSACH and MED1 PMID:34709441
• The Journal of biological chemistry • 2000 • Cartilage oligomeric matrix protein is a calcium-binding protein, and a mutation in its type 3 repeats causes conformational changes. PMID:10852928
• The Journal of biological chemistry • 2001 • Mutations in cartilage oligomeric matrix protein causing pseudoachondroplasia and multiple epiphyseal dysplasia affect binding of calcium and collagen I, II, and IX. PMID:11084047
• The American journal of pathology • 2003 • Mutation (D472Y) in the type 3 repeat domain of cartilage oligomeric matrix protein affects its early vesicle trafficking in endoplasmic reticulum and induces apoptosis. PMID:12819015
• BMC medical genetics • 2018 • Pathogenic gene screening in 91 Chinese patients with short stature of unknown etiology with a targeted next-generation sequencing panel. PMID:30541462

Evidence Based Scoring (AI generated)