ACAN – Osteochondritis Dissecans

Osteochondritis dissecans is characterized by focal lesions of articular cartilage and subchondral bone that detach from the joint surface. Familial cases with autosomal dominant inheritance implicate the aggrecan gene (ACAN) in disease etiology, highlighting its role in cartilage extracellular matrix integrity. The initial report described a heterozygous missense mutation in the C-type lectin domain (c.6907G>A (p.Val2303Met)) co-segregating with disease across five generations in eight affected relatives (PMID:20137779).

Subsequently, three additional unrelated pedigrees with dominant osteochondritis dissecans were found to harbor novel missense variants clustering in the aggrecan G3 domain, all impairing secretion and extracellular matrix binding (PMID:35338222). In total, four families provide strong evidence for autosomal dominant inheritance of ACAN-related osteochondritis dissecans, with consistent segregation of pathogenic missense alleles affecting the C-type lectin repeat.

A recent case report described a heterozygous frameshift variant c.5391dup (p.Ser1644LeufsTer18) in a boy with multi-focal osteochondritis dissecans and short stature, expanding the variant spectrum to include loss-of-function alleles and reinforcing haploinsufficiency as a pathogenic mechanism (PMID:36950254).

Functional assays have demonstrated that G3 domain missense variants (e.g., p.Val2303Met) abrogate binding to fibulin-1, fibulin-2, and tenascin-R, and mass spectrometric analysis confirms incorporation of mutant aggrecan into cartilage but with defective matrix interactions. Secretion assays further show reduced extracellular release of variant aggrecan, supporting a dominant-negative mechanism disrupting cartilage structure (PMID:20137779; PMID:35338222).

No studies to date have provided conflicting evidence. The convergent genetic and experimental data establish a consistent link between heterozygous ACAN variants and autosomal dominant osteochondritis dissecans.

Key Take-home: Heterozygous ACAN variants, particularly missense changes in the G3 domain, cause autosomal dominant osteochondritis dissecans by disrupting aggrecan secretion and extracellular matrix binding, providing a clear target for genetic diagnosis and familial counseling.

References

• American journal of human genetics • 2010 • A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans. PMID:20137779
• Scientific reports • 2022 • Novel missense ACAN gene variants linked to familial osteochondritis dissecans cluster in the C-terminal globular domain of aggrecan. PMID:35338222
• Bone Reports • 2023 • From "ACAN" to "I CAN": Restoring wellness in a boy with severe osteochondritis dissecans through diagnostic precision combined with optimal medical, surgical and rehabilitation management. PMID:36950254

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