Connexins are
integral membrane proteins forming aqueous gap junction channels that allow the diffusional exchange of
ions and small metabolites between cells, thus coordinating metabolic activities in multicellular tissues. Dominant mutations in the Cx26 gene GJB2 have been shown to cause
keratitis-
ichthyosis-
deafness (
KID) syndrome,
palmoplantar keratoderma associated with
hearing loss, and
Vohwinkel syndrome. Missense mutations in the closely related Cx30 gene GJB6 underlie
Clouston syndrome (
autosomal dominant hidrotic ectodermal dysplasia). We report a 6-y-old boy with phenotypic characteristics of
KID syndrome as well as atrichia. In contrast to other
KID syndrome patients, molecular analysis of the
connexin gene GJB2 did not disclose a pathogenic mutation, although the patient was homozygous for a common polymorphism (V27I) in the coding sequence of Cx26. Nevertheless, screening of GJB6 revealed a heterozygous missense mutation (V37E) predicted to alter sequence and charge of the first transmembrane helix of Cx30, which was previously implicated in
Clouston syndrome (Smith et al, 2002). The presence of a pathogenic Cx30 mutation and the lack of a pathologic molecular change in Cx26 in this patient, whose clinical features predominantly resemble
KID syndrome, suggest genetic heterogeneity of
KID syndrome and underscore that mutations in Cx30, similar to those in Cx26 or Cx31, can cause different phenotypes. Based on our results,
connexin gene mutations should be considered in patients presenting with congenital
sensorineural hearing loss and disorders of cornification, and screening of several
connexin genes with known cutaneous phenotype, such as those for Cx26, Cx30, Cx30.3, and Cx31, may be required.