TY - JOUR
T1 - Expanding the phenotypic spectrum of Cx26 disorders
T2 - Bart-Pumphrey syndrome is caused by a novel missense mutation in GJB2
AU - Richard, Gabriele
AU - Brown, Nkecha
AU - Ishida-Yamamoto, Akemi
AU - Krol, Alfons
N1 - Funding Information:
The authors are grateful to the family members who participated in our study and to Drs. Bart and Pumphrey for stimulating discussions. We thank Pyrosequencing Inc., Westborough, MA, for technical support. This study was supported in part by NIH/NIAMS grants K08-AR02141 and P01-AR38923, the National Foundation for Ectodermal Dysplasias, the American Skin Association and the Dermatology Foundation (GR).
PY - 2004/11
Y1 - 2004/11
N2 - 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.
AB - 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.
KW - Bart-Pumphrey syndrome
KW - Connexin 26
KW - Gap junction proteins
KW - Knuckle pads
KW - Leukonychia
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U2 - 10.1111/j.0022-202X.2004.23470.x
DO - 10.1111/j.0022-202X.2004.23470.x
M3 - Article
C2 - 15482471
AN - SCOPUS:6344225698
SN - 0022-202X
VL - 123
SP - 856
EP - 863
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 5
ER -