Genetic Heterogeneity of KID Syndrome: Identification of a Cx30 Gene (GJB6) Mutation in a Patient with KID Syndrome and Congenital Atrichia

Abstract

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.

Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response

“…Dominantly inherited missense mutations in Cx26 and Cx30 result in multiple overlapping skin disorders characterized by hyperkeratosis (47,48). CX26 and CX30 share 89% amino acid similarity and are directly adjacent on human chromosome 13.…”

“…The number of positive cells in 250 consecutive basal cells was counted and averaged in 3 nonoverlapping skin sections. Frozen sections were hybridized with CD3, CD4, and CD8 antibodies as previously described (47). For Western blot analysis, newborn skin was snap-frozen in liquid nitrogen and pulverized.…”

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…Hystrix skin changes can be observed in other ichthyoses, eg, KID syndrome (Table XII), or in particular types of ectodermal dysplasia. 69 The annular EI (Fig 3, E ), which is a result of KRT1 or KRT10 mutations, 70,71 is classified as a clinical variant of EI.…”

“…In some cases, it may overlap with Clouston syndrome, which is caused by mutations in GJB6 (connexin 30). 69,122 One could argue that NS 123 (Fig 5, H ) should not be classified with the ichthyoses, because it is characterized by premature desquamation and a thinner rather than thicker stratum corneum (SC). However, the clinical features often overlap with the CIE phenotype, and scaling is a common clinical feature.…”

Growth Characteristics of Children With Ectodermal Dysplasia Syndromes

“…Most children (n ϭ 102; 72%) had a clinical diagnosis of HED (Christ-Siemens-Touraine syndrome). 11 The remainder had 1 of the following diagnoses: ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome (n ϭ 6), 12 Clouston syndrome (n ϭ 3), 13 Rapp-Hodgkin syndrome (n ϭ 4), 14 oculodentodigital syndrome (n ϭ 3), 15 hidrotic ectodermal dysplasia (n ϭ 1), Hay-Wells syndrome (n ϭ 4), 16 keratitis-ichthyosisdeafness syndrome (n ϭ 1), 17 Gorlin-Goltz syndrome (n ϭ 1), 18 pachyonychia congenita (n ϭ 1), 19 or unclassified (n ϭ 12).…”