A new, recurrent mutation of GJB3 (Cx31) in erythrokeratodermia variabilis
S.M. Morley
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorM.I. White
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorM. Rogers
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorD. Wasserman
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorP. Ratajczak
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorW.H.I. Mclean
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorG. Richard
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorS.M. Morley
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorM.I. White
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorM. Rogers
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorD. Wasserman
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorP. Ratajczak
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorW.H.I. Mclean
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorG. Richard
Department of Dermatology, Ninewells Hospital, Dundee, U.K. *Department of Dermatology, Aberdeen Royal Infirmary, Aberdeen, U.K.†Department of Dermatology, The Children's Hospital at Westmead, Sydney, Australia‡Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, 233 S 10th St, BLSB Suite 409, Philadelphia, PA 19107, U.S.A.§Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, U.K.
Search for more papers by this authorConflicts of interest: None declared.
Summary
Background Erythrokeratodermia variabilis (EKV) is an autosomal dominant or recessive genodermatosis characterized by the coexistence of randomly occurring, transient, erythematous patches and hyperkeratosis of the skin. The disorder has been mapped to chromosome 1p35.1 but is genetically heterogeneous. EKV may be caused by pathogenic mutations in one of two neighbouring connexin genes, GJB3 and GJB4, encoding the gap junction proteins Cx31 and Cx30.3, respectively. Twelve distinct mutations identified to date cluster either at the cytoplasmic amino-terminus or in the four transmembrane domains.
Objectives To report a large family with EKV and an unrelated sporadic case.
Methods DNA amplification and mutation analysis, followed by denaturing high-performance liquid chromatography to confirm the segregation of the mutations in the two families with EKV.
Results A novel, recurrent GJB3 mutation (625C→T; L209F) was identified in the family with EKV and in the unrelated sporadic case.
Conclusions This mutation is the first to affect a conserved residue in the cytoplasmic carboxy-terminus of any connexin gene with a cutaneous phenotype, emphasizing its structural and/or functional importance.
References
- 1 De Buy Wenninger LM. Erythrokeratodermie congenitale ichthyosiforme avec hyperepidermotrophie in verslagen van vereeningingene. Nederl Tijdschr Geneesk 1907; 1A: 510–5.
- 2 Mendes da Costa S. Erythro- et keratodermia variabilis in a mother and a daughter. Acta Derm Venereol (Stockh) 1925; 6: 255–61.
- 3 Richard G, Ringpfeil F. Erythrokeratodermia variabilis. In: Dermatology ( JL Bolognia, JL Jorizzo, RP Rapini, eds), Vol. 1. Philadelphia: Mosby, 2003; 799–800.
- 4 Richard G, Brown N, Rouan F et al. Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype–phenotype correlations. J Invest Dermatol 2003; 120: 601–9.DOI: 10.1046/j.1523-1747.2003.12080.x
- 5 Terrinoni A, Leta A, Pedicelli C et al. A novel recessive connexin 31 (GJB3) mutation in a case of erythrokeratodermia variabilis. J Invest Dermatol 2004; 122: 837–9.DOI: 10.1111/j.0022-202X.2004.22311.x
- 6 Gottfried I, Landau M, Glaser F et al. A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein. Hum Mol Genet 2002; 11: 1311–6.DOI: 10.1093/hmg/11.11.1311
- 7 Richard G, Lin JP, Smith L et al. Linkage studies in erythrokeratodermias: fine mapping, genetic heterogeneity and analysis of candidate genes. J Invest Dermatol 1997; 109: 666–71.DOI: 10.1111/1523-1747.ep12337713
- 8 Macari F, Landau M, Cousin P et al. Mutation in the gene for connexin 30.3 in a family with erythrokeratodermia variabilis. Am J Hum Genet 2000; 67: 1296–301.
- 9 Van Der Schroeff JG, Nijenhuis LE, Meera Khan P et al. Genetic linkage between erythrokeratodermia variabilis and Rh locus. Hum Genet 1984; 68: 165–8.DOI: 10.1007/BF00279308
- 10 Richard G, Smith LE, Bailey RA et al. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet 1998; 20: 366–9.DOI: 10.1038/3840
- 11 Di WL, Rugg EL, Leigh IM et al. Multiple epidermal connexins are expressed in different keratinocyte subpopulations including connexin 31. J Invest Dermatol 2001; 117: 958–64.DOI: 10.1046/j.0022-202x.2001.01468.x
- 12 Plantard L, Huber M, Macari F et al. Molecular interaction of connexin 30.3 and connexin 31 suggests a dominant-negative mechanism associated with erythrokeratodermia variabilis. Hum Mol Genet 2003; 12: 3287–94.DOI: 10.1093/hmg/ddg364
- 13 Ishida-Yamamoto A, Kelsell D, Common J et al. A case of erythrokeratoderma variabilis without mutations in connexin 31. Br J Dermatol 2000; 143: 1283–7.DOI: 10.1046/j.1365-2133.2000.03902.x
- 14 Arita K, Akiyama M, Tsuji Y et al. Erythrokeratoderma variabilis without connexin 31 or connexin 30.3 gene mutation: immunohistological, ultrastructural and genetic studies. Acta Derm Venereol (Stockh) 2003; 83: 266–70.DOI: 10.1080/00015550310016517
- 15 Richards B, Skoletsky J, Shuber AP et al. Multiplex PCR amplification from the CFTR gene using DNA prepared from buccal brushes/swabs. Hum Mol Genet 1993; 2: 159–63.
- 16 Richard G, Brown N, Smith LE et al. The spectrum of mutations in erythrokeratodermias—novel and de novo mutations in GJB3. Hum Genet 2000; 106: 321–9.DOI: 10.1007/s004390051045
- 17 Wilgoss A, Leigh IM, Barnes MR et al. Identification of a novel mutation R42P in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis. J Invest Dermatol 1999; 113: 1119–22.DOI: 10.1046/j.1523-1747.1999.00792.x
- 18 Rouan F, Lo CW, Fertala A et al. Divergent effects of two sequence variants of GJB3 (G12D and R32W) on the function of connexin 31 in vitro. Exp Dermatol 2003; 12: 191–7.DOI: 10.1034/j.1600-0625.2003.120210.x
- 19 Diestel S, Richard G, Doring B et al. Expression of a connexin31 mutation causing erythrokeratodermia variabilis is lethal for HeLa cells. Biochem Biophys Res Commun 2002; 296: 721–8.DOI: 10.1016/S0006-291X(02)00929-4
- 20 Di WL, Monypenny J, Common JE et al. Defective trafficking and cell death is characteristic of skin disease-associated connexin 31 mutations. Hum Mol Genet 2002; 11: 2005–14.DOI: 10.1093/hmg/11.17.2005
- 21 VanSlyke JK, Deschenes SM, Musil LS. Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins. Mol Biol Cell 2000; 11: 1933–46.
- 22 Rouan F, Yi LS, Uitto J et al. Pathogenic mutations affecting Cx31and Cx30.3 impair gap junction function and induce cell death in vitro. J Invest Dermatol 2003; 121: A603.
- 23 Seeman P, Mazanec R, Vondrácek P et al. Novel mutations in the GJB1-connexin 32 (Cx32) gene in Czech CMTX patients. Eur J Hum Genet 2004; 12: 248.
- 24 Lopez-Bigas N, Rabionet R, Martinez E et al. Identification of seven novel SNPS (five nucleotide and two amino acid substitutions) in the connexin31 (GJB3) gene. Hum Mutat 2000; 15: 481–2.DOI: 10.1002/(SICI)1098-1004(200005)15:5<481::AID-HUMU15>3.0.CO;2-7
