Human Molecular Genetics, 1999, Vol. 8, No. 7 1237-1243
© 1999 Oxford University Press
A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel’s syndrome) in three unrelated families
1Wellcome Trust Centre for Human Genetics, University of Oxford, Windmill Road, Oxford OX3 7BN, UK, 2Klinik und Poliklinik für Dermatologie und Venerologie, Universität zu Köln, Germany, 3Catedra de Dermatologia, Universidad de Granada, Avenida de Madrid 11, 18012 Granada, Spain, 4Istituto di Genetica Medica, Dipartimento di Medicina Sperimentale e Diagnostica, Ferrara, Italy, 5Istituto di Scienze Dermatologiche, IRCCS, Università di Milano, Italy and 6Department of Dermatology, Southern General Hospital, Glasgow G51 4TF, UK
The multiplicity of functions served by intercellular gap junctions is reflected by the variety of phenotypes caused by mutations in the connexins of which they are composed. Mutations in the connexin26 (Cx26) gene (GJB2) at 13q11–q13 are a major cause of autosomal recessive hearing loss (DFNB1), but have also been reported in autosomal dominant deafness (DFNA3). We now report a Cx26 mutation in three families with mutilating keratoderma and deafness [Vohwinkel’s syndrome (VS; MIM 124500), as originally described]. VS is characterized by papular and honeycomb keratoderma associated with constrictions of digits leading to autoamputation, distinctive starfish-like acral keratoses and moderate degrees of deafness. In a large British pedigree, we have mapped the defect to the Cx26 locus. All 10 affected members were heterozygous for a non-conservative mutation, D66H, in Cx26. The same mutation was found subsequently in affected individuals from two unrelated Spanish and Italian pedigrees segregating VS, suggesting that D66H in Cx26 is a common mutation in classical VS. This mutation occurs at a highly conserved residue in the first extracellular domain of the Cx26 molecule, and may exert its effects by interfering with assembly into connexons, docking with adjacent cells or gating properties of the gap junction. Our results provide evidence that a specific mutation in Cx26 can impair epidermal differentiation, as well as inner ear function.
a To whom correspondence should be addressed. Tel: +44 1865 740021; Fax: +44 1865 742186; Email: maestrin{at}well.ox.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. SINHA and S. B. WATSON Keratoderma Hereditarium Mutilans (Vohwinkel Syndrome) J Hand Surg Eur Vol., April 1, 2009; 34(2): 235 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E A de Zwart-Storm, H Hamm, J Stoevesandt, P M Steijlen, P E Martin, M van Geel, and M A M van Steensel A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness J. Med. Genet., March 1, 2008; 45(3): 161 - 166. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Gerido, A. M. DeRosa, G. Richard, and T. W. White Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness Am J Physiol Cell Physiol, July 1, 2007; 293(1): C337 - C345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hibino and Y. Kurachi Molecular and physiological bases of the k+ circulation in the Mammalian inner ear. Physiology, October 1, 2006; 21: 336 - 345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Arita, M. Akiyama, T. Aizawa, Y. Umetsu, I. Segawa, M. Goto, D. Sawamura, M. Demura, K. Kawano, and H. Shimizu A Novel N14Y Mutation in Connexin26 in Keratitis-Ichthyosis-Deafness Syndrome: Analyses of Altered Gap Junctional Communication and Molecular Structure of N Terminus of Mutated Connexin26 Am. J. Pathol., August 1, 2006; 169(2): 416 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. K. Haass, E. Wladykowski, S. Kief, I. Moll, and J. M. Brandner Differential Induction of Connexins 26 and 30 in Skin Tumors and Their Adjacent Epidermis J. Histochem. Cytochem., February 1, 2006; 54(2): 171 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N J Leonard, A L Krol, S Bleoo, and M J Somerville Sensorineural hearing loss, striate palmoplantar hyperkeratosis, and knuckle pads in a patient with a novel connexin 26 (GJB2) mutation J. Med. Genet., January 1, 2005; 42(1): e2 - e2. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Thomas, D. Telford, and D. W. Laird Functional Domain Mapping and Selective Trans-dominant Effects Exhibited by Cx26 Disease-causing Mutations J. Biol. Chem., April 30, 2004; 279(18): 19157 - 19168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Martinez-Mir, A Zlotogorski, D Londono, D Gordon, A Grunn, E Uribe, L Horev, I M Ruiz, N O Davalos, O Alayan, et al. Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24 J. Med. Genet., December 1, 2003; 40(12): 872 - 878. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. Kretz, C. Euwens, S. Hombach, D. Eckardt, B. Teubner, O. Traub, K. Willecke, and T. Ott Altered connexin expression and wound healing in the epidermis of connexin-deficient mice J. Cell Sci., August 15, 2003; 116(16): 3443 - 3452. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Bakirtzis, R. Choudhry, T. Aasen, L. Shore, K. Brown, S. Bryson, S. Forrow, L. Tetley, M. Finbow, D. Greenhalgh, et al. Targeted epidermal expression of mutant Connexin 26(D66H) mimics true Vohwinkel syndrome and provides a model for the pathogenesis of dominant connexin disorders Hum. Mol. Genet., July 15, 2003; 12(14): 1737 - 1744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. K. Marziano, S. O. Casalotti, A. E. Portelli, D. L. Becker, and A. Forge Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30 Hum. Mol. Genet., April 15, 2003; 12(8): 805 - 812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Provost, M. Moreau, A. Leturque, and C. Nizard Ultraviolet A radiation transiently disrupts gap junctional communication in human keratinocytes Am J Physiol Cell Physiol, January 1, 2003; 284(1): C51 - C59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bitner-Glindzicz Hereditary deafness and phenotyping in humans Br. Med. Bull., October 1, 2002; 63(1): 73 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-L. Di, J. Monypenny, J. E.A. Common, C. T.C. Kennedy, K. A. Holland, I. M. Leigh, E. L. Rugg, D. Zicha, and D. P. Kelsell Defective trafficking and cell death is characteristic of skin disease-associated connexin 31 mutations Hum. Mol. Genet., August 15, 2002; 11(17): 2005 - 2014. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Gottfried, M. Landau, F. Glaser, W.-L. Di, J. Ophir, B. Mevorah, N. Ben-Tal, D. P. Kelsell, and K. B. Avraham A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein Hum. Mol. Genet., May 16, 2002; 11(11): 1311 - 1316. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Stratigos and H. P. Baden Unraveling the Molecular Mechanisms of Hair and Nail Genodermatoses Arch Dermatol, November 1, 2001; 137(11): 1465 - 1471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Priolo and C. Lagana Ectodermal dysplasias: a new clinical-genetic classification J. Med. Genet., September 1, 2001; 38(9): 579 - 585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Lopez-Bigas, M. Olive, R. Rabionet, O. Ben-David, J. A. Martinez-Matos, O. Bravo, I. Banchs, V. Volpini, P. Gasparini, K. B. Avraham, et al. Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment Hum. Mol. Genet., April 1, 2001; 10(9): 947 - 952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Rouan, T. W. White, N. Brown, A. M. Taylor, T. W. Lucke, D. L. Paul, C. S. Munro, J. Uitto, M. B. Hodgins, and G. Richard trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation J. Cell Sci., January 6, 2001; 114(11): 2105 - 2113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E. Norgett, S. J. Hatsell, L. Carvajal-Huerta, J.-C. Ruiz Cabezas, J. Common, P. E. Purkis, N. Whittock, I. M. Leigh, H. P. Stevens, and D. P. Kelsell Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma Hum. Mol. Genet., November 1, 2000; 9(18): 2761 - 2766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Suga, M. Jarnik, P. S. Attar, M. A. Longley, D. Bundman, A. C. Steven, P. J. Koch, and D. R. Roop Transgenic Mice Expressing a Mutant Form of Loricrin Reveal the Molecular Basis of the Skin Diseases, Vohwinkel Syndrome and Progressive Symmetric Erythrokeratoderma J. Cell Biol., October 18, 2000; 151(2): 401 - 412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Bouadjar, S. Benmazouzia, J.-F. Prud'homme, S. Cure, and J. Fischer Clinical and Genetic Studies of 3 Large, Consanguineous, Algerian Families With Mal de Meleda Arch Dermatol, October 1, 2000; 136(10): 1247 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Pal, X. Liu, D. Mackay, A. Shiels, V. M. Berthoud, E. C. Beyer, and L. Ebihara Connexin46 mutations linked to congenital cataract show loss of gap junction channel function Am J Physiol Cell Physiol, September 1, 2000; 279(3): C596 - C602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Morlé, M. Bozon, N. Alloisio, P. Latour, A. Vandenberghe, H. Plauchu, L. Collet, P. Edery, J. Godet, and G. Lina-Granade A novel C202F mutation in the connexin26 gene (GJB2) associated with autosomal dominant isolated hearing loss J. Med. Genet., May 1, 2000; 37(5): 368 - 370. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. B. Presland and B. A. Dale Epithelial Structural Proteins of the Skin and Oral Cavity: Function in Health and Disease Critical Reviews in Oral Biology & Medicine, January 1, 2000; 11(4): 383 - 408. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Heathcote, P. Syrris, N. D Carter, and M. A Patton A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis (MIM 148350) J. Med. Genet., January 1, 2000; 37(1): 50 - 51. [Abstract] [Full Text]
|
|