CCN2 – Spondyloepimetaphyseal Dysplasia

The extracellular matrix–associated protein CCN2 plays a critical role in skeletal development by stimulating osteogenesis and regulating cartilage matrix composition. Spondyloepimetaphyseal dysplasia (SEMD) is a skeletal dysplasia characterized by short stature, premature osteoarthritis, and osteoporosis in childhood. Despite CCN2’s known involvement in bone biology, human phenotypes linked to CCN2 variants had not been described until recently.

In a cohort of families with unexplained SEMD, a heterozygous signal peptide variant in CCN2 (c.65G>C (p.Arg22Pro)) was identified in 14 affected subjects with varying degrees of short stature, premature osteoarthritis, and osteoporosis ([PMID:39414788]). The c.65G>C (p.Arg22Pro) variant segregated in multiple kindreds and was absent in population databases, supporting its pathogenicity. Inheritance was autosomal dominant, with all carriers displaying the SEMD phenotype.

Functional studies revealed that patient‐derived cell lines harboring c.65G>C (p.Arg22Pro) showed significantly reduced secretion of CCN2 protein and increased intracellular retention, indicating impaired signal peptide processing and export. This secretion defect weakened CCN2’s ability to stimulate osteogenic differentiation of bone marrow mesenchymal stem cells in vitro.

Animal models further corroborated the human findings: zebrafish ccn2a knockout embryos exhibited reduced bone mineralization, and osteoblast lineage–specific Ccn2 conditional knockout mice (Ccn2fl/fl;Prx1Cre) developed low bone mass, abnormal growth plate architecture, decreased bone formation, and increased bone resorption, mirroring key aspects of the human skeletal phenotype.

Collectively, these data establish haploinsufficiency of CCN2 via a monoallelic c.65G>C (p.Arg22Pro) variant as a novel cause of autosomal dominant SEMD. The concordance between genetic segregation, in vitro secretion assays, and animal model phenotypes provides a robust framework for diagnostic evaluation and genetic counseling in patients presenting with low bone mass and metaphyseal anomalies.

Key Take-home: Screening for heterozygous CCN2 signal peptide variants should be considered in individuals with SEMD, as functional assays and animal models confirm impaired CCN2 secretion as the pathogenic mechanism.

References

• Bone Research | 2024 | A monoallelic variant in CCN2 causes an autosomal dominant spondyloepimetaphyseal dysplasia with low bone mass PMID:39414788

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