GJA1 – Craniometaphyseal Dysplasia

Craniometaphyseal dysplasia (CMD) is a rare sclerosing skeletal disorder characterised by progressive hyperostosis of craniofacial bones and metaphyseal flaring of long bones. Autosomal recessive (AR) CMD had been mapped to 6q21-22, but the causative gene remained unknown until identification of GJA1 variants. GJA1 encodes connexin43 (Cx43), a major gap junction protein expressed in osteoblasts, osteocytes, osteoclasts and chondrocytes that mediates intercellular diffusion of low molecular weight molecules.

In a multi-family study, whole-exome sequencing of an AR CMD proband revealed a novel homozygous missense variant, c.716G>A (p.Arg239Gln), in GJA1. This variant was confirmed in six affected individuals from four unrelated families and exhibited complete cosegregation with CMD under an AR inheritance model (PMID:23951358). Affected subjects presented with classic CMD features without ocular or dental anomalies typical of oculodentodigital dysplasia.

Segregation analysis showed that all affected relatives were homozygous for c.716G>A (p.Arg239Gln), whereas unaffected family members were heterozygous carriers. No other pathogenic GJA1 coding variants were identified in screened CMD cohorts, underscoring the specificity of p.Arg239Gln for AR CMD.

Connexin43 is abundantly expressed in bone-forming cells. Tissue-specific distribution studies demonstrated phosphorylation-dependent heterogeneity of Cx43 in osteoblast-like cells and other tissues, indicating regulated channel assembly and function ([PMID:1846023]). Additionally, Tbx2 represses the GJA1 promoter in osteoblastic-like cells via T-box binding sites, linking transcriptional control of Cx43 to osteoblast differentiation and bone remodeling ([PMID:15354864]).

Although direct functional assays of the p.Arg239Gln variant in bone models are pending, the mutation lies in the conserved C-terminal domain critical for channel phosphorylation and assembly. Disruption of Cx43 function in other models leads to skeletal abnormalities, supporting a loss-of-function mechanism in AR CMD.

Overall, genetic and experimental data provide moderate clinical validity for biallelic GJA1 p.Arg239Gln as a cause of autosomal recessive CMD. Additional functional studies in bone cells will further clarify pathogenic mechanisms and inform diagnostic and therapeutic strategies.

Key Take-home: Biallelic GJA1 p.Arg239Gln disrupts connexin43-mediated gap junction communication in bone cells, establishing a clinically actionable diagnosis for AR CMD.

References

• PloS One | 2013 | A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia. PMID:23951358
• Molecular and cellular biology | 1991 | Tissue-specific distribution of differentially phosphorylated forms of Cx43. PMID:1846023
• Calcified tissue international | 2004 | Tbx2 represses expression of Connexin43 in osteoblastic-like cells. PMID:15354864

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