HID and KID syndromes are associated with the same connexin 26 mutation

Abstract

We show that KID and HID syndromes are identical at the molecular level and confirm the clinical impression that these syndromes are one and the same. That previous clinical reports made a distinction may be a consequence of sampling artefacts; alternatively, genetic background effects such as the presence of concurrent mutations in other skin-expressed genes may modify the phenotype.

R75Q dominant mutation in GJB2 gene silenced by the in cis recessive mutation c.35delG

“…Digenic transmission has been, in fact, observed for GJB2 and GJB6, a different gene lying at the same locus of the gene GJB2, codifying for the connexin 30 protein (Cx30) [del Castillo et al, 2005]. Cx26 is also involved in dominant forms of hearing loss [Denoyelle et al, 1998] and in syndromic disorders where deafness can be found associated with problems in skin [Van Geel et al, 2002;Iossa et al, 2009]. It is not simple to identify the etiology of hearing loss; detection of Cx26 mutations does not always indicate the involvement of the gene in the cause of the deafness: some deaf patients only have a mutation on one allele, while others have mutations that are not known to be definitively pathologic.…”

Progress in Understanding GJB2-Linked Deafness

“…Dominant GJB2 mutations cause mild to profound hearing impairment, commonly progressive in nature and variably associated with skin disorders [19, 20, 21, 22]. While recessive GJB2 mutations are scattered along the entire protein, most GJB2 dominant mutations, leading both to nonsyndromic hearing impairment and to skin pathologies, are clustered within or near the first extracellular domain of the protein.…”

“…Syndromic features associated with deafness consist mainly of varying skin phenotypes including palmoplantar keratoderma, Vohwinkel syndrome and keratitis-ichthyosis/hystrix-like ichthyosis-deafness (KID-HID) [19, 20, 21, 22]. More than 90 different GJB2 deafness-causing mutations have been reported since, including splice, nonsense, missense and frameshift mutations (a complete and updated list of GJB2 mutations is reported in The Connexin-Deafness Homepage – World wide web URL: http://www.crg.es/deafness), most of which are quite rare.…”

G59S mutation in theGJB2 (connexin 26) gene in a patient with Bart-Pumphrey syndrome

“…Heterozygous missense mutations in GJB2 were found in several conditions associating deafness and hyperkeratosis: D66H in mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome, OMIM 124500) [Maestrini et al, 2002], G59A and R75Q in palmoplantar hyperkeratosis with deafness (PPKD, OMIM 148350) [Heathcote et al, 2000;Uyguner et al, 2002], as well as D50Y and D50N in keratitisichthyosis-deafness syndrome (KID, OMIM 148210), and in hystrix like-ichthyosis-deafness syndrome (HID, OMIM 602540) [Richard et al, 2002;van Geel et al, 2002;Yotsumoto et al, 2003]. Richard et al [2002] also described two sporadic cases of KID syndrome with G12R and S17F missense mutations, each patient showing a different mutation.…”