MATN3 – Multiple Epiphyseal Dysplasia

Matrilin‑3 (MATN3) has been robustly associated with multiple epiphyseal dysplasia, a skeletal dysplasia characterized by delayed and irregular ossification of epiphyses, joint pain, and early‑onset osteoarthritis (PMID:12884427). Multiple independent studies across diverse populations have identified pathogenic missense mutations in MATN3 that consistently co‐segregate with the disorder, supporting its clinical relevance for diagnostic decision‑making.

The clinical presentation in affected individuals includes joint locking symptoms, abnormal cartilage architecture, and variable degrees of short stature, with radiological analyses demonstrating distinctive epiphyseal anomalies (PMID:38800255). Detailed family studies reveal autosomal dominant inheritance with several affected relatives in multiple pedigrees, underscoring the importance of segregation data in establishing causality (PMID:32264862).

Genetic evidence is substantial; case reports and multi‐patient studies have documented MATN3 mutations in over 20 unrelated probands, with several families showing clear segregation of the variant with the disease phenotype (PMID:15459972) and positive familial history (PMID:15523498). One representative pathogenic variant reported is c.382G>C (p.Ala128Pro), which has been identified in multiple affected individuals and serves as a diagnostic marker in current genetic testing algorithms.

Functional studies further corroborate the genetic findings. In vitro assays consistently demonstrate that mutant MATN3 proteins misfold and are retained within the endoplasmic reticulum, leading to impaired secretion and subsequent disruption of extracellular matrix integrity (PMID:16199550; PMID:16287128). These alterations in protein trafficking and structure explain the cartilage defects observed in patients, aligning the experimental data with clinical phenotypes.

Additional studies highlight genotype–phenotype correlations and even note that, while the majority of MATN3 mutations result in a classic MED phenotype, certain variants may lead to distinct clinical presentations, such as spondyloepimetaphyseal dysplasia, suggesting that the degree of MATN3 dysfunction can variably affect skeletal development (PMID:39293509). Despite these nuances, the overall weight of evidence supports a strong association between MATN3 mutations and multiple epiphyseal dysplasia.

In summary, the genetic and functional data converge to establish MATN3 as a critical gene in the pathogenesis of multiple epiphyseal dysplasia. The integration of case reports, multi‐patient cohorts, and in vitro functional assessments provides a cohesive narrative that is instrumental for clinical diagnostic strategies, commercial assay development, and future research publications.

Key Take‑home sentence: MATN3 mutation testing offers a powerful and reliable diagnostic tool for confirming multiple epiphyseal dysplasia, ensuring improved patient management and advancing translational research.

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
• BMC musculoskeletal disorders • 2020 • A novel p.A191D matrilin‑3 variant in a Vietnamese family with multiple epiphyseal dysplasia: a case report PMID:32264862
• Cureus • 2024 • Multiple Epiphyseal Dysplasia With Knee Joint Locking Symptoms Caused by Intra‑articular Loose Bodies PMID:38800255
• Human mutation • 2004 • Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia PMID:15459972
• European journal of human genetics : EJHG • 2005 • Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations PMID:15523498
• Journal of medical genetics • 2005 • Matrilin‑3 mutations that cause chondrodysplasias interfere with protein trafficking while a mutation associated with hand osteoarthritis does not PMID:16199550
• Human mutation • 2005 • Multiple epiphyseal dysplasia mutations in MATN3 cause misfolding of the A‑domain and prevent secretion of mutant matrilin‑3 PMID:16287128

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