Expanding the phenotypic spectrum of Cx26 disorders: Bart-Pumphrey syndrome is caused by a novel missense mutation in GJB2.
Bart-Pumphrey syndrome (BPS) is an autosomal dominant disorder characterized by sensorineural hearing loss, palmoplantar keratoderma, knuckle pads, and leukonychia, which show considerable phenotypic variability. The clinical features partially overlap with Vohwinkel syndrome and Keratitis-Ichthyosis-Deafness syndrome, both disorders caused by dominant mutations in the GJB2 gene encoding the gap junction protein connexin-26, suggesting an etiological relationship. We report here a novel GJB2 mutation N54K segregating in a family with BPS, which was not detected in 110 control individuals of Northern European ancestry. This non-conservative missense mutation lies within a cluster of pathogenic GJB2 mutations affecting the evolutionary conserved first extracellular loop of Cx26 important for docking of connexin hemichannels and voltage gating. Immunostaining of Cx26 in lesional palmar and knuckle skin was weak or absent, although its adnexal expression appeared normal and the punctate membrane staining of Cx26 and other epidermal connexins was not altered. Nevertheless, the widespread immunostaining of Cx30 throughout the spinous cell layers suggested a compensatory overexpression. Our results emphasize that pleiotropic GJB2 mutations are responsible for at least 5 overlapping dermatological disorders associated with syndromic hearing loss and cover a wide range of severity and organ involvement.
Department of Dermatology and Cutaneous Biology, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. gabriele.richard@jefferson.edu
Gabriele
G
Richard
Nkecha
N
Brown
Akemi
A
Ishida-Yamamoto
Alfons
A
Krol
D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012867:Skin / Q000473:pathology; D013577:Syndrome
D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26