MATN3 – multiple epiphyseal dysplasia type 5

Multiple epiphyseal dysplasia type 5 (MED5) is a rare autosomal dominant skeletal dysplasia characterized by delayed and irregular epiphyseal ossification, joint pain, stiffness, and progression to early-onset osteoarthritis. The MATN3 gene encodes matrilin-3, an extracellular matrix protein critical for cartilage integrity. Heterozygous pathogenic variants in MATN3 cluster in the von Willebrand factor A-domain, disrupting protein folding and secretion.

Initial evidence from a multigenerational family with bilateral hereditary micro-epiphyseal dysplasia confirmed linkage to MATN3 and identified a missense variant c.382G>C (p.Ala128Pro) segregating with disease in multiple affected family members (PMID:12884427). A second, de novo intragenic tandem duplication of exons 2–5 was detected in a sporadic MED5 case, demonstrating recurrence of MATN3 involvement in distinct lineages (PMID:30080953). Overall, two unrelated probands support a robust genotype–phenotype correlation.

The variant spectrum in MED5 includes missense substitutions in the A-domain (e.g., c.382G>C (p.Ala128Pro)), as well as rare copy number duplications. All pathogenic alleles localize to the single A-domain, with no recurrent founder variants reported and population frequencies below detection thresholds.

Functional assays in primary chondrocytes demonstrate that A-domain missense mutations (e.g., c.361C>T (p.Arg121Trp), c.656C>A (p.Ala219Asp), c.653A>G (p.Tyr218Cys), c.400G>A (p.Glu134Lys)) lead to intracellular retention and endoplasmic reticulum stress, preventing matrilin-3 secretion (PMID:16287128). Structural studies reveal a Zn²⁺-dependent conformational switch in the A-domain essential for collagen binding, with mutations abolishing proper folding (PMID:17881354). Mouse models harboring the V194D substitution recapitulate ER aggregation, unfolded protein response activation, and chondrodysplasia pathology (PMID:23956175).

Mechanistically, mutant matrilin-3 exerts a dominant-negative effect by misfolding in the A-domain, triggering ER stress and UPR-mediated chondrocyte dysfunction. XBP1 signaling mitigates aggregate accumulation in growth plate chondrocytes, and its disruption exacerbates skeletal defects in Matn3 knock-in mice (PMID:31260448).

Integration of genetic segregation, de novo occurrence, and concordant functional data supports a ClinGen Moderate clinical validity classification for the MATN3–MED5 association. Key Take-Home: MATN3 sequencing should be prioritized in patients with suspected MED5 to enable molecular diagnosis and inform potential UPR-targeted therapies.

References

• American journal of medical genetics. Part A • 2003 • Familial multiple epiphyseal dysplasia due to a matrilin-3 mutation: further delineation of the phenotype including 40 years follow-up. PMID:12884427
• Human mutation • 2018 • Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias. PMID:30080953
• Human mutation • 2005 • Multiple epiphyseal dysplasia mutations in MATN3 cause misfolding of the A-domain and prevent secretion of mutant matrilin-3. PMID:16287128
• The Journal of biological chemistry • 2007 • Structural and functional characterization of recombinant matrilin-3 A-domain and implications for human genetic bone diseases. PMID:17881354
• Human molecular genetics • 2013 • Armet/Manf and Creld2 are components of a specialized ER stress response provoked by inappropriate formation of disulphide bonds: implications for genetic skeletal diseases. PMID:23956175
• PLoS genetics • 2019 • XBP1 signalling is essential for alleviating mutant protein aggregation in ER-stress related skeletal disease. PMID:31260448

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