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GJB6 – Keratitis-Ichthyosis-Deafness Syndrome

A single 6-year-old boy presenting with the hallmark triad of vascularizing keratitis, ichthyosiform erythrokeratoderma and sensorineural hearing loss, as well as congenital atrichia, was found to carry a heterozygous GJB6 c.110T>A (p.Val37Glu) variant, without concomitant GJB2 pathogenic changes (1 proband) (PMID:15140211). This expands the genetic heterogeneity of KID syndrome by implicating connexin-30 in a phenotype classically attributed to connexin-26.

Functional characterization of Cx30 V37E in keratinocyte and HeLa models demonstrated impaired plasma membrane trafficking and failure to form gap junction plaques, consistent with a loss-of-function defect (PMID:12419304). Subsequent studies revealed that V37E-Cx30 is retained in the endoplasmic reticulum and triggers apoptosis in epidermal cells, highlighting a pathogenic mechanism distinct from other Cx30 mutations (PMID:24522190).

References

  • The Journal of investigative dermatology • 2004 • Genetic heterogeneity of KID syndrome: identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. PMID:15140211
  • Biochemical and biophysical research communications • 2002 • Functional studies of human skin disease- and deafness-associated connexin 30 mutations. PMID:12419304
  • Journal of cell science • 2014 • Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies. PMID:24522190

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single unrelated proband with heterozygous GJB6 V37E variant ([PMID:15140211]); no segregation data

Genetic Evidence

Limited

One proband reported with c.110T>A (p.Val37Glu) in GJB6 leading to KID syndrome ([PMID:15140211])

Functional Evidence

Moderate

In vitro studies show impaired trafficking and apoptotic gain-of-function for V37E-Cx30 in keratinocytes and HeLa cells ([PMID:12419304; PMID:24522190])