COL12A1 – Bethlem Myopathy 2

COL12A1 encodes the α1 chain of collagen XII, a fibril-associated collagen involved in extracellular matrix (ECM) organization. Pathogenic variants in COL12A1 have been linked to Bethlem Myopathy 2, an autosomal dominant myopathic Ehlers-Danlos overlap syndrome characterized by muscle weakness, joint contractures, and connective tissue abnormalities (COL12A1; Bethlem Myopathy 2).

To date, 24 patients from 15 unrelated families have been reported with COL12A1-related Bethlem Myopathy 2, including 14 families with autosomal dominant inheritance and one family with autosomal recessive inheritance (PMID:37353357; PMID:31273343). Segregation of pathogenic variants has been observed across multiple affected relatives, supporting a strong genetic association (9 additional affected relatives). A representative pathogenic splice-site variant is c.5893C>T (p.Arg1965Cys), which localizes to the collagenous domain critical for fibril assembly.

The variant spectrum includes missense substitutions clustering in the von Willebrand factor A and collagenous domains (12 distinct missense changes), splice-site defects (6 variants), small in-frame exon-skipping deletions (4 defects), and protein-truncating alleles (5 variants). Recurrent and family-specific alleles highlight both de novo dominant-negative effects and loss-of-function mechanisms.

Functional studies in patient-derived fibroblasts demonstrate intracellular retention of mutant collagen XII and impaired secretion of the long isoform, with near-absence of the short isoform and altered ECM composition, including decreased decorin and tenascin-X levels (PMID:31273343; PMID:27348394). These cellular phenotypes recapitulate key aspects of the human phenotype and support a disease mechanism involving aberrant ECM organization.

No conflicting evidence has been reported that disputes the role of COL12A1 variants in Bethlem Myopathy 2. The totality of genetic segregation, allelic heterogeneity, and concordant functional data yields strong clinical validity.

Integration of genetic and experimental findings confirms that pathogenic COL12A1 variants cause Bethlem Myopathy 2 via dominant-negative and loss-of-function mechanisms. COL12A1 genetic testing is therefore recommended for patients presenting with a myopathic Ehlers-Danlos phenotype, enhancing diagnostic precision and informing clinical management.

References

• American Journal of Medical Genetics Part A | 2023 | Homozygous splice site variant affecting the first von Willebrand factor A domain of COL12A1 in a patient with myopathic Ehlers-Danlos syndrome. PMID:37353357
• Genetics in Medicine | 2020 | Novel defects in collagen XII and VI expand the mixed myopathy/Ehlers-Danlos syndrome spectrum and lead to variant-specific alterations in the extracellular matrix. PMID:31273343
• Muscle & Nerve | 2017 | Novel Col12A1 variant expands the clinical picture of congenital myopathies with extracellular matrix defects. PMID:27348394

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