Expanding The Phenotypic Spectrum of Cx26 Disorders: Bart–Pumphrey Syndrome is Caused by a Novel Missense Mutation in GJB2
2004; Elsevier BV; Volume: 123; Issue: 5 Linguagem: Inglês
10.1111/j.0022-202x.2004.23470.x
ISSN1523-1747
AutoresGabriele Richard, Nkecha Brown, Akemi Ishida‐Yamamoto, Alfons Krol,
Tópico(s)Hearing, Cochlea, Tinnitus, Genetics
ResumoBart–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. 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. Bart–Pumphrey syndrome gap junction protein connexin-26 palmoplantar keratoderma sensorineural hearing loss Thirty-seven years ago in the New England Journal of Medicine, the dermatologist Bart and otolaryngologist Pumphrey described a new autosomal dominant syndrome characterized by knuckle pads, leukonychia, palmoplantar keratoderma (PPK), and deafness segregating in a 6-generation family, and disputed whether this complex phenotype could be a monogenic defect with pleiotropic expression (Bart and Pumphrey, 1967Bart R.S. Pumphrey R.E. Knuckle pads, leukonychia and deafness. A dominantly inherited syndrome.N Engl J Med. 1967; 276: 202-207Crossref PubMed Scopus (77) Google Scholar). Recognized as a distinct form of ectodermal dysplasia and syndromic PPK (OMIM#149200), several families and sporadic cases have been reported since, often with a striking and partially age-dependent variability in clinical features between family members (Schwann, 1963Schwann J. Keratosis palmaris et plantaris with congenital deafness and total leukonychia.Dermatologica. 1963; 126: 335-353Crossref PubMed Scopus (14) Google Scholar;Crosby and Vidurrizaga, 1976Crosby E.F. Vidurrizaga R.H. Knuckle pads, leukonychia, deafness, and keratosis palmoplantaris: Report of a family.Johns Hopkins Med J. 1976; 139: 90-92PubMed Google Scholar;Crosti et al., 1983Crosti C. Sala F. Bertani E. Gasparini G. Menni S. Leukonychia totalis and ectodermal dysplasia. Report of 2 cases.Ann Dermatol Venereol. 1983; 110: 617-622PubMed Google Scholar;Ramer et al., 1994Ramer J.C. Vasily D.B. Ladda R.L. Familial leuconychia, knuckle pads, hearing loss, and palmoplantar hyperkeratosis: An additional family with Bart–Pumphrey syndrome.J Med Genet. 1994; 31: 68-71Crossref PubMed Scopus (25) Google Scholar;Kose and Baloglu, 1996Kose O. Baloglu H. Knuckle pads, leukonychia and deafness.Int J Dermatol. 1996; 35: 728-729Crossref PubMed Scopus (10) Google Scholar). The coexistence of prelingual sensorineural hearing loss (SNHL) and an inherited disorder of cornification is relatively rare. Only 11 families with SNHL/PPK have been reported to date, none of which developed knuckle pads, leukonychia or other abnormalities (Bititci, 1975Bititci O.Ö. Familial hereditary, progressive sensori-neural hearing loss with keratosis palmaris and palntaris.J Laryngol Otol. 1975; 89: 1143-1146Crossref PubMed Scopus (18) Google Scholar;Frentz et al., 1976Frentz G. Everberg G. Wulf H.C. Congenital perceptive hearing loss and atopic dermatitis.Acta Otolaryngol. 1976; 82: 242-244Crossref PubMed Scopus (7) Google Scholar;Hatamochi et al., 1982Hatamochi A. Nakagawa S. Ueki H. Miyoshi K. Iuchi I. Diffuse palmoplantar keratoderma with deafness.Arch Dermatol. 1982; 118: 605-607https://doi.org/10.1001/archderm.118.8.605Crossref PubMed Scopus (22) Google Scholar;Sharland et al., 1992Sharland M. Bleach N.R. Goberdhan P.D. Patton M.A. Autosomal dominant palmoplantar hyperkeratosis and sensorineural deafness in three generations.J Med Genet. 1992; 29: 50-52Crossref PubMed Scopus (30) Google Scholar;Fitzgerald and Verbov, 1996Fitzgerald D.A. Verbov J.L. Hereditary palmoplantar keratoderma with deafness.J Dermatol. 1996; 134: 939-942https://doi.org/10.1046/j.1365-2133.1996.133868.xCrossref Google Scholar;Richard et al., 1998Richard G. White T.W. Smith L.E. et al.Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma.Hum Genet. 1998; 103: 393-399https://doi.org/10.1007/s004390050839Crossref PubMed Scopus (233) Google Scholar;Sevior et al., 1998Sevior K.B. Hatamochi A. Stewart I.A. et al.Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness.Am J Med Genet. 1998; 75: 179-185https://doi.org/10.1002/(SICI)1096-8628(19980113)75:2 3.3.CO;2-1Crossref PubMed Scopus (0) Google Scholar;Heathcote et al., 2000Heathcote K. Syrris P. Carter N.D. Patton M.A. A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis.J Med Genet. 2000; 37: 50-51https://doi.org/10.1136/jmg.37.1.50Crossref PubMed Scopus (111) Google Scholar;Kelsell et al., 2000Kelsell D.P. Wilgoss A.L. Richard G. Stevens H.P. Munro C.S. Leigh I.M. Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family.Eur J Hum Genet. 2000; 8: 141-144https://doi.org/10.1038/sj.ejhg.5200407Crossref PubMed Scopus (64) Google Scholar;Martin et al., 2000Martin L. Toutain A. Guillen C. et al.Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome.Br J Dermatol. 2000; 143: 876-883https://doi.org/10.1046/j.1365-2133.2000.03797.xCrossref PubMed Scopus (27) Google Scholar;Rouan et al., 2001Rouan F. White T.W. Brown N. et al.Trans-dominant inhibition of connexin-43 by mutant connexin-26: Implications for dominant connexin disorders affecting epidermal differentiation.J Cell Sci. 2001; 114: 2105-2113Crossref PubMed Google Scholar;Uyguner et al., 2002Uyguner O. Tukel T. Baykal C. et al.The novel R75Q mutation in the GJB2 gene causes autosomal dominant hearing loss and palmoplantar keratoderma in a Turkish family.Clin Genet. 2002; 62: 306-309https://doi.org/10.1034/j.1399-0004.2002.620409.xCrossref PubMed Scopus (62) Google Scholar). Molecular studies revealed in three of these families with focal plaques of PPK a common point mutation (A7445G) in the extrachromosomal mitochondrial genome (mtDNA) (Sevior et al., 1998Sevior K.B. Hatamochi A. Stewart I.A. et al.Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness.Am J Med Genet. 1998; 75: 179-185https://doi.org/10.1002/(SICI)1096-8628(19980113)75:2 3.3.CO;2-1Crossref PubMed Scopus (0) Google Scholar;Martin et al., 2000Martin L. Toutain A. Guillen C. et al.Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome.Br J Dermatol. 2000; 143: 876-883https://doi.org/10.1046/j.1365-2133.2000.03797.xCrossref PubMed Scopus (27) Google Scholar), while point mutations in the connexin-26 (Cx26) gene, GJB2, on chromosome 13q11–q12 were detected in five families with variable forms of PPK (Richard et al., 1998Richard G. White T.W. Smith L.E. et al.Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma.Hum Genet. 1998; 103: 393-399https://doi.org/10.1007/s004390050839Crossref PubMed Scopus (233) Google Scholar;Heathcote et al., 2000Heathcote K. Syrris P. Carter N.D. Patton M.A. A connexin 26 mutation causes a syndrome of sensorineural hearing loss and palmoplantar hyperkeratosis.J Med Genet. 2000; 37: 50-51https://doi.org/10.1136/jmg.37.1.50Crossref PubMed Scopus (111) Google Scholar;Kelsell et al., 2000Kelsell D.P. Wilgoss A.L. Richard G. Stevens H.P. Munro C.S. Leigh I.M. Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family.Eur J Hum Genet. 2000; 8: 141-144https://doi.org/10.1038/sj.ejhg.5200407Crossref PubMed Scopus (64) Google Scholar;Rouan et al., 2001Rouan F. White T.W. Brown N. et al.Trans-dominant inhibition of connexin-43 by mutant connexin-26: Implications for dominant connexin disorders affecting epidermal differentiation.J Cell Sci. 2001; 114: 2105-2113Crossref PubMed Google Scholar;Uyguner et al., 2002Uyguner O. Tukel T. Baykal C. et al.The novel R75Q mutation in the GJB2 gene causes autosomal dominant hearing loss and palmoplantar keratoderma in a Turkish family.Clin Genet. 2002; 62: 306-309https://doi.org/10.1034/j.1399-0004.2002.620409.xCrossref PubMed Scopus (62) Google Scholar). More often, PPK and SNHL are associated with other distinct features, such as digital circular constriction bands and pseudoainhum in autosomal dominant Vohwinkel syndrome, also known as mutilating keratoderma (OMIM#124500) (Vohwinkel, 1929Vohwinkel K.H. Keratoma hereditarium mutilans.Arch Dermatol Syph. 1929; 158: 354-364Crossref Scopus (68) Google Scholar). In Keratitis–Ichthyosis–Deafness syndrome (KIDS; OMIM#148210), PPK and SNHL are accompanied by corneal defects and neovascularization, follicular hyperkeratoses, generalized thickening of the skin or symmetrically distributed erythematous and hyperkeratotic plaques. In addition, an increased susceptibility to mucocutaneous infections and squamous cell carcinoma has been noted (Caceres-Rios et al., 1996Caceres-Rios H. Tamayo-Sanchez L. Duran-Mckinster C. de la Luz Orozco M. Ruiz-Maldonado R. Keratitis, ichthyosis, and deafness (KID syndrome): Review of the literature and proposal of a new terminology.Pediatr Dermatol. 1996; 13: 105-113Crossref PubMed Scopus (137) Google Scholar). The rare occurrence of partial leukonychia or knuckle pads in KIDS (Jurecka et al., 1985Jurecka W. Aberer E. Mainitz M. Jurgensen O. Keratitis, ichthyosis, and deafness syndrome with glycogen storage.Arch Dermatol. 1985; 121: 799-801https://doi.org/10.1001/archderm.121.6.799Crossref PubMed Google Scholar;Shiraishi et al., 1994Shiraishi S. Murakami S. Miki Y. Oral fluconazole treatment of fungating candidiasis in the keratitis, ichthyosis and deafness (KID) syndrome.Br J Dermatol. 1994; 131: 904-907Crossref PubMed Scopus (20) Google Scholar;Kone-Paut et al., 1998Kone-Paut I. Hesse S. Palix C. et al.Keratitis, ichthyosis, and deafness (KID) syndrome in half sibs.Pediatr Dermatol. 1998; 15: 219-221https://doi.org/10.1046/j.1525-1470.1998.1998015219.xCrossref PubMed Scopus (23) Google Scholar) emphasizes the clinical overlap with Bart–Pumphrey syndrome (BPS). The molecular cause of both Vohwinkel and KID syndrome are distinct germline mutations in GJB2 encoding the gap junction protein connexin-26 (Cx26) (Maestrini et al., 1999Maestrini E. Korge B.P. Ocana-Sierra J. et al.A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families.Hum Mol Genet. 1999; 8: 1237-1243https://doi.org/10.1093/hmg/8.7.1237Crossref PubMed Scopus (274) Google Scholar;Kelsell et al., 2000Kelsell D.P. Wilgoss A.L. Richard G. Stevens H.P. Munro C.S. Leigh I.M. Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family.Eur J Hum Genet. 2000; 8: 141-144https://doi.org/10.1038/sj.ejhg.5200407Crossref PubMed Scopus (64) Google Scholar;Richard et al., 2002Richard G. Rouan F. Willoughby C.E. et al.Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis–ichthyosis–deafness syndrome.Am J Hum Genet. 2002; 70: 1341-1348https://doi.org/10.1086/339986Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar;van Steensel et al., 2002van Steensel M.A. van Geel M. Nahuys M. Smitt J.H. Steijlen P.M. A novel connexin 26 mutation in a patient diagnosed with keratitis–ichthyosis-deafness syndrome.J Invest Dermatol. 2002; 118: 724-727https://doi.org/10.1046/j.1523-1747.2002.01735.xCrossref PubMed Scopus (126) Google Scholar). Therefore, we have investigated a family with BPS and report here a novel pathogenic GJB2 (Cx26) mutation, confirming that BPS stems from an underlying defect in an epithelial connexin gene. Our results broaden the phenotypic spectrum of Cx26 mutations and illustrate their intriguing pleiotropic effects. We studied a multigeneration BPS family originating in Poland (Figure 1). All affected family members, including the maternal grandmother and uncle, consistently presented with congenital deafness and developed diffuse, sharply demarcated thickening of the skin of palms and soles during early childhood (Figure 2). In the proband, an audiogram at 24 y of age demonstrated profound bilateral SNHL with normal middle ear function. The PPK had locally an almost punctate surface reminiscent of VS, and was most profound over the heels and in interphalangeal folds, resulting there in the formation of hard, hyperkeratotic bands (Figure 2b, c). Before puberty, individuals II-1 and III-1 had developed fixed, hyperkeratotic plaques with a verrucous surface over the metacarpo- and interphalangeal joints (knuckle pads) that regressed over time in II-1 (Figure 2a, d). III-1 had leukonychia of all nails, which was also present, albeit to a much lesser degree, in II-1 (Figure 2a, d). The nails of other affected family members were reportedly normal. There was no evidence for abnormalities involving mucous membranes, hair, sweat glands and vision or any other organ manifestations. Light microscopic examination (Figure 2e) of skin biopsies from the left palm and a metacarpal knuckle pad of individual III-1 revealed similar pathological features, including massive orthokeratotic hyperkeratosis without evidence for retained nuclei, hypergranulosis, acanthosis, and papillomatosis. Epidermal gap junctions appeared normal on electron microscopic evaluation (Figure 2f).Figure 2Clinical features of Bart–Pumphrey syndrome (BPS). (a) III-1. 24-y-old man with leukonychia, hyperkeratotic, verruciform plaques over metacarpo- and interphalangeal joints (knuckle pads) and (b) diffuse palmoplantar keratoderma with formation of hard, keratotic bands in the interphalangeal folds. (c) II-1. 58-y-old mother of III-1. Note the rough, grainy surface of the plantar keratoderma and (d) the lack of knuckle pads and very discrete leukonychia of the right hand. (e). Photomicrograph of a skin biopsy of a knuckle pad (H&E stain) shows compact orthokeratotic hyperkeratosis, hypergranulosis, and acanthosis of the epidermis. (f) Transmission electron micrograph demonstrating a normal-appearing gap junction plaque between granular keratinocytes.View Large Image Figure ViewerDownload (PPT) Mutation analysis of GJB2 revealed in both affected individuals II-1 and III-1 a heterozygous C to A substitution at nucleotide 162 (from the ATG start site) in codon 54. This point mutation is predicted to lead to a non-conservative replacement of asparagine 54 (AAC) with a negatively charged lysine (AAA) (N54K, Figure 1a) in the first extracellular loop of Cx26. The co-segregation of N54K with BPS in the proband's family was confirmed by pyrosequencing (data not shown), and the mutation was excluded in 110 unrelated controls of Northern European origin without evidence for skin disorders or hearing loss by pyrosequencing or direct DNA sequencing. These results, together with data compiled from thousands of individuals tested for GJB2 variants worldwide (see The Connexin-Deafness Homepage), evidently excluded the possibility of N54K being a non-consequential sequence polymorphism and strongly support the causative role of N54K in BPS. Sequence alignment of human Cx26 with the other 19 members of the connexin family in man and in other species demonstrated that asparagine is almost invariably present at this position in the first extracellular loop and evolutionary highly conserved (Figure 1b). To investigate if sequence variants in other epidermally expressed connexin genes might modify the clinical phenotype in BPS, we also screened the genes encoding Cx30, Cx30.3, Cx31, Cx31.1, and Cx43. III-1 was heterozygous for the silent polymorphism N119N in GJB3 (Cx31) with a frequency of 3% for the minor thymidine allele in a control population (Richard et al., 2000Richard G. Brown N. Smith L.E. et al.The spectrum of mutations in erythrokeratodermias—novel and de novo mutations in GJB3.Hum Genet. 2000; 106: 321-329https://doi.org/10.1007/s004390051045Crossref PubMed Scopus (76) Google Scholar), but no other sequence aberrations were found. To assess the invivo effects of mutation N54K on the cutaneous gap junction system, we performed immunohistochemical analyses of Cx26, Cx30, and Cx43 on frozen sections of palmar and knuckle lesional skin of the proband. Similar to normal interfollicular epidermis, Cx26 immunostaining was absent in the hyperkeratotic and acanthotic knuckle epidermis (Figure 3a). In palmar skin, Cx26 staining was irregular and weak, limited to a few foci in the spinous layers (Figure 3d). Nonetheless, epithelial cells of eccrine sweat glands and sweat ducts demonstrated a distinct, punctate, plasma membrane staining of Cx26, which widely overlapped with that of Cx30 (Figure 3f) as in normal control skin. Epidermal keratinocytes surrounding the eccrine sweat ducts showed focal points of co-localization of both Cx43 and Cx26 in lesional skin (Figure 3g). There was no detectable cytoplasmic accumulation of Cx26 nor Cx30 or Cx43 in the cells, suggesting that the mutant Cx26 might be either rapidly degraded or properly transferred to the cell membranes. In contrast to Cx26, Cx30 staining was much more intense and widespread compared with normal skin and extended to the spinous cell layers (Figure 3b). The distribution of Cx43 appeared normal with a strong punctate membrane staining throughout the spinous and granular layers as well as weak staining in basal keratinocytes (Figure 3c). These observations suggested that mutation N54K resulted in reduced epidermal Cx26 expression with compensatory overexpression of Cx30 albeit it did apparently not interfere with the formation of Cx30 and Cx43-containing gap junctions. Human connexin 26 belongs to a multigenic family of 20 structural proteins forming gap junctions, clusters of intercellular channels that permit the diffusional exchange of ions and small metabolites between adjoining cells (Willecke et al., 2002Willecke K. Eiberger J. Degen J. et al.Structural and functional diversity of connexin genes in the mouse and human genome.Biol Chem. 2002; 383: 725-737Crossref PubMed Scopus (967) Google Scholar). This direct intercellular communication system plays an important role for control and coordination of tissue morphogenesis, differentiation, and growth, and fulfills a multitude of tissue-specific functions. Cx26 is widely expressed in most tissues of the human body, including the ectodermally derived epithelia of cochlea, cornea, and skin (Salomon et al., 1994Salomon D. Masgrau E. Vischer S. et al.Topography of mammalian connexins in human skin.J Invest Dermatol. 1994; 103: 240-247https://doi.org/10.1111/1523-1747.ep12393218Crossref PubMed Scopus (121) Google Scholar;Forge et al., 1999Forge A. Becker D. Casalotti S. et al.Gap junctions and connexin expression in the inner ear.Novartis Found Symp. 1999; 219: 134-150PubMed Google Scholar;Lucke et al., 1999Lucke T. Choudhry R. Thom R. Selmer I.S. Burden A.D. Hodgins M.B. Upregulation of connexin 26 is a feature of keratinocyte differentiation in hyperproliferative epidermis, vaginal epithelium, and buccal epithelium.J Invest Dermatol. 1999; 112: 354-361https://doi.org/10.1046/j.1523-1747.1999.00512.xCrossref PubMed Scopus (129) Google Scholar;Richard et al., 2002Richard G. Rouan F. Willoughby C.E. et al.Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis–ichthyosis–deafness syndrome.Am J Hum Genet. 2002; 70: 1341-1348https://doi.org/10.1086/339986Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar). The complete loss of Cx26 protein or its function due to recessive mutations in GJB2 is the singlemost common cause of non-syndromic SNHL in man (Rabionet et al., 2002Rabionet R. Lopez-Bigas N. Arbones M.L. Estivill X. Connexin mutations in hearing loss, dermatological and neurological disorders.Trends Mol Med. 2002; 8: 205-212https://doi.org/10.1016/S1471-4914(02)02327-4Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). In mice, the targeted ablation of Cx26 in the inner ear (Cohen-Salmon et al., 2002Cohen-Salmon M. Ott T. Michel V. et al.Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment and cell death.Curr Biol. 2002; 9: 1106-1111Abstract Full Text Full Text PDF Scopus (343) Google Scholar), as well as the transgenic expression of a dominant-negative Cx26 mutation (R75W) (Kudo et al., 2003Kudo T. Kure S. Ikeda K. et al.Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.Hum Mol Genet. 2003; 12: 995-1004https://doi.org/10.1093/hmg/ddg116Crossref PubMed Scopus (124) Google Scholar), revealed a progressive degeneration of the sensory hair cells ensuing from deformed supporting cells and loss of the tunnel of Corti, possibly due to disturbed cortilymph homeostasis. These findings vividly illustrate the essential function of Cx26 for the auditory process in the inner ear, though different connexin proteins apparently compensate for Cx26 in all other organs, including the skin. The latter organ utilizes up to 10 different connexin proteins (Di et al., 2001Di W.L. Rugg E.L. Leigh I.M. Kelsell D.P. Multiple epidermal connexins are expressed in different keratinocyte subpopulations including connexin 31.J Invest Dermatol. 2001; 117: 958-964https://doi.org/10.1046/j.0022-202x.2001.01468.xCrossref PubMed Google Scholar). Under normal circumstances Cx26 expression is limited to the palmoplantar epidermis, sweat glands and ducts, and hair follicles. Upregulation of Cx26 in response to wounding, tape stripping, treatment with retinoids and in hyperproliferative epidermal disorders such as psoriasis (Masgrau-Peya et al., 1997Masgrau-Peya E. Salomon D. Saurat J.H. Meda P. In vivo modulation of connexins 43 and 26 of human epidermis by topical retinoic acid treatment.J Histochem Cytochem. 1997; 45: 1207-1215Crossref PubMed Scopus (48) Google Scholar;Labarthe et al., 1998Labarthe M.P. Bosco D. Saurat J.H. Meda P. Salomon D. Upregulation of connexin 26 between keratinocytes of psoriatic lesions.J Invest Dermatol. 1998; 111: 72-76https://doi.org/10.1046/j.1523-1747.1998.00248.xCrossref PubMed Scopus (95) Google Scholar;Lucke et al., 1999Lucke T. Choudhry R. Thom R. Selmer I.S. Burden A.D. Hodgins M.B. Upregulation of connexin 26 is a feature of keratinocyte differentiation in hyperproliferative epidermis, vaginal epithelium, and buccal epithelium.J Invest Dermatol. 1999; 112: 354-361https://doi.org/10.1046/j.1523-1747.1999.00512.xCrossref PubMed Scopus (129) Google Scholar;Coutinho et al., 2003Coutinho P. Qiu C. Frank S. Tamber K. Becker D. Dynamic changes in connexin expression correlate with key events in the wound healing process.Cell Biol Int. 2003; 27: 525-541Crossref PubMed Scopus (141) Google Scholar), however, implicates Cx26 in growth regulation, migration, and differentiation of keratinocytes. Although the mere loss of Cx26 is not sufficient to produce a skin disorder, autosomal dominant mutations of the Cx26 gene may manifest with various cutaneous and extracutaneous findings, perhaps due to their dominant-negative effect on wild-type Cx26 and other connexins as determined in vitro (Richard et al., 1998Richard G. White T.W. Smith L.E. et al.Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma.Hum Genet. 1998; 103: 393-399https://doi.org/10.1007/s004390050839Crossref PubMed Scopus (233) Google Scholar;Martin et al., 1999Martin P.E. Coleman L.S. Casalotti S.O. Forge A. Evans W.H. Properties of connexin26 gap junctional proteins derived from mutations associated with non-syndromal heriditary deafness.Hum Mol Genet. 1999; 8: 2369-2376https://doi.org/10.1093/hmg/8.13.2369Crossref PubMed Scopus (116) Google Scholar;Rouan et al., 2001Rouan F. White T.W. Brown N. et al.Trans-dominant inhibition of connexin-43 by mutant connexin-26: Implications for dominant connexin disorders affecting epidermal differentiation.J Cell Sci. 2001; 114: 2105-2113Crossref PubMed Google Scholar;Forge et al., 2003Forge A. Marziano N.K. Casalotti S.O. Becker D.L. Jagger D. The inner ear contains heteromeric channels composed of cx26 and cx30 and deafness-related mutations in cx26 have a dominant negative effect on cx30.Cell Commun Adhes. 2003; 10: 341-346Crossref PubMed Google Scholar;Marziano et al., 2003Marziano N.K. Casalotti S.O. Portelli A.E. Becker D.L. Forge A. Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30.Hum Mol Genet. 2003; 12: 805-812https://doi.org/10.1093/hmg/ddg076Crossref PubMed Scopus (142) Google Scholar) and invivo (Bakirtzis et al., 2003Bakirtzis G. Choudhry R. Aasen T. 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. 2003; 12: 1737-1744Crossref PubMed Scopus (60) Google Scholar). In this study, we demonstrate that BPS is the fifth defined phenotype attributable to dominant GJB2 mutations. We report a novel pathogenic GJB2 mutation (162C>A) substituting a highly conserved asparagine with lysine (N54K) in the first extracellular loop of Cx26, which leads to congenital SNHL, PPK, prominent knuckle pads, and leukonychia. Thus, 37 y after the recognition of this rare syndrome, our results provide molecular evidence supporting Bart and Pumphrey's hypothesis of a single genetic defect with pleiotropic expression. It remains to be seen, however, if the amino acid replacement, N54K, is consistently associated with a BPS phenotype, in analogy to mutation D66H in Vohwinkel syndrome, or if BPS may be caused by different GJB2 mutations, as is the case in KID syndrome. In fact, the range of phenotypic presentations of autosomal dominant GJB2 mutations is intriguing. They form an allelic series including non-syndromic SNHL (W44C, W44S, R75W, R75Q, D179N, R184Q, and C202F), SNHL associated with diffuse or transgredient PPK (E42del, G59R, R75W, and R75Q) Vohwinkel syndrome (D66H), KID syndrome (D50N, D50Y), and now BPS (N54K) (Richard, 2003aRichard G. Connexin gene pathology.Clin Exp Dermatol. 2003; 28: 397-409https://doi.org/10.1046/j.1365-2230.2003.01312.xCrossref PubMed Scopus (57) Google Scholar) (see also The Connexin-Deafness Homepage). Tissue involvement and severity span a broad range from non-syndromic SNHL affecting the inner ear alone to the multisystemic disorder KIDS syndrome, which may affect cochlea (SNHL), skin (PPK, erythrokeratoderma), cornea (keratitis, corneal neovascularization), hair follicles (hypo-and atrichosis), teeth and nails, and increases the risk for squamous cell carcinoma (Caceres-Rios et al., 1996Caceres-Rios H. Tamayo-Sanchez L. Duran-Mckinster C. de la Luz Orozco M. Ruiz-Maldonado R. Keratitis, ichthyosis, and deafness (KID syndrome): Review of the literature and proposal of a new terminology.Pediatr Dermatol. 1996; 13: 105-113Crossref PubMed Scopus (137) Google Scholar). Hence it seems conceivable that Cx26 gene mutations may play a pathogenic role in yet other disorders with partially overlapping features, such as autosomal recessive Heimler syndrome (OMIM 234580) characterized by SNHL, leukonychia and other nail findings, autosomal-dominant SNHL associated with nail dystrophy (OMIM 124480) or, less likely, leukonychia totalis hereditaria (OMIM 151,600) and familial
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