GJB2 – Palmoplantar Keratoderma-Deafness Syndrome

Autosomal dominant mutations in GJB2 encode connexin-26 (Cx26), a gap-junction protein expressed in epidermis and cochlea. Dominant variants can cause syndromic hearing loss with palmoplantar keratoderma (PPKDFN) through dominant-negative effects on gap junctional intercellular communication (PMID:35938034).

A Chinese female with severe palmoplantar hyperkeratosis and delayed-onset sensorineural hearing loss was found to harbor a novel heterozygous GJB2 variant c.224G>C (p.Arg75Pro) (PMID:35938034). Parental testing revealed low-level mosaicism in her mildly affected mother, confirming autosomal dominant inheritance with segregation in one additional relative. To date, this is the only reported family with the p.Arg75Pro allele in PPKDFN.

The p.Arg75Pro change lies at the EC1-TM2 junction, a mutational hotspot for syndromic Cx26 variants, and structural modeling predicts disruption of channel stability and permeability, consistent with a dominant-negative mechanism disrupting Cx26-mediated junctions (PMID:35938034). Similar dominant-negative behavior has been demonstrated for other EC1 variants in PPKDFN, supporting functional concordance.

Key take-home: Screening for heterozygous and low-level mosaic GJB2 variants—particularly at the EC1-TM2 hotspot—is essential for accurate diagnosis and genetic counseling in PPKDFN.

References

• Frontiers in Genetics • 2022 • Case Report: A Novel GJB2 Missense Variant Inherited From the Low-Level Mosaic Mother in a Chinese Female With Palmoplantar Keratoderma With Deafness. PMID:35938034

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