COMP – Pseudoachondroplasia

Pseudoachondroplasia (PSACH) is an autosomal dominant spondylo-epi-metaphyseal dysplasia characterized by disproportionate short-limb short stature (HP:0008873), joint laxity and early-onset osteoarthritis. Heterozygous mutations in COMP, encoding cartilage oligomeric matrix protein, underlie PSACH and some allelic forms of multiple epiphyseal dysplasia (MED).

1. Clinical Validity (Definitive)

COMP mutations have been reported in over 250 unrelated PSACH and MED probands across more than 30 independent publications, with consistent co-segregation in multiplex families and concordant functional data demonstrating protein misfolding and ER retention ([PMID:7670471], [PMID:9463320]).

2. Genetic Evidence (Strong)

Inheritance: Autosomal dominant.

Segregation: 19 additional affected relatives segregating COMP variants [PMID:9463320].

Case series: >250 probands with heterozygous, in-frame deletions or missense substitutions clustered in the calcium-binding type 3 repeats, including recurrent hotspots (e.g., p.Asp473del) and private variants.

Variant spectrum: In-frame single-amino-acid deletions (e.g., p.Asp473del), missense substitutions of conserved Asp/Cys residues, small insertions within CLR domains.

Representative variant: c.1414G>C (p.Asp472His) ([PMID:7670471]).

3. Functional / Experimental Evidence (Strong)

PSACH-associated COMP variants disrupt calcium binding, alter domain conformation, and cause intracellular retention in rER vesicles, triggering ER stress, reduced chondrocyte proliferation and increased apoptosis in vitro and in knock-in mouse models ([PMID:10753957], [PMID:22006726]). In cell culture, mutant COMP shows dominant-negative interference with extracellular matrix assembly.

4. Conflicting Evidence

No studies have refuted the COMP–PSACH association. All reported variants cluster in functional domains with consistent pathogenic mechanisms.

5. Integration & Clinical Utility

COMP fulfills definitive ClinGen criteria for PSACH: abundant genetic evidence with clear autosomal dominant segregation, variant clustering in calcium-binding repeats, and robust functional concordance demonstrating misfolding, ER stress and chondrocyte apoptosis. Genetic testing for COMP variants enables accurate diagnosis, prognostic counseling and informs management, including orthopedic surveillance and growth monitoring.

Key Take-home: Heterozygous COMP mutations cause PSACH by a dominant-negative mechanism; molecular confirmation guides diagnosis and family counseling.

References

• Nature Genetics • 1995 • Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. PMID:7670471
• American Journal of Human Genetics • 1998 • Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia–multiple epiphyseal dysplasia disease spectrum. PMID:9463320
• The Journal of Biological Chemistry • 2000 • A cartilage oligomeric matrix protein mutation associated with pseudoachondroplasia changes the structural and functional properties of the type 3 domain. PMID:10753957
• Human Mutation • 2012 • A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia. PMID:22006726

Evidence Based Scoring (AI generated)