Genetic Heterogeneity of KID Syndrome: Identification of a Cx30 Gene (GJB6) Mutation in a Patient with KID Syndrome and Congenital Atrichia
2004; Elsevier BV; Volume: 122; Issue: 5 Linguagem: Inglês
10.1111/j.0022-202x.2004.22518.x
ISSN1523-1747
AutoresAmy Y. Jan, Shivan Amin, Paulina Ratajczak, Gabriele Richard, Virginia P. Sybert,
Tópico(s)Neuroscience of respiration and sleep
ResumoConnexins are integral membrane proteins forming aqueous gap junction channels that allow the diffusional exchange of ions and small metabolites between cells, thus coordinating metabolic activities in multicellular tissues. Dominant mutations in the Cx26 gene GJB2 have been shown to cause keratitis-ichthyosis-deafness (KID) syndrome, palmoplantar keratoderma associated with hearing loss, and Vohwinkel syndrome. Missense mutations in the closely related Cx30 gene GJB6 underlie Clouston syndrome (autosomal dominant hidrotic ectodermal dysplasia). We report a 6-y-old boy with phenotypic characteristics of KID syndrome as well as atrichia. In contrast to other KID syndrome patients, molecular analysis of the connexin gene GJB2 did not disclose a pathogenic mutation, although the patient was homozygous for a common polymorphism (V27I) in the coding sequence of Cx26. Nevertheless, screening of GJB6 revealed a heterozygous missense mutation (V37E) predicted to alter sequence and charge of the first transmembrane helix of Cx30, which was previously implicated in Clouston syndrome (Smith et al, 2002). The presence of a pathogenic Cx30 mutation and the lack of a pathologic molecular change in Cx26 in this patient, whose clinical features predominantly resemble KID syndrome, suggest genetic heterogeneity of KID syndrome and underscore that mutations in Cx30, similar to those in Cx26 or Cx31, can cause different phenotypes. Based on our results, connexin gene mutations should be considered in patients presenting with congenital sensorineural hearing loss and disorders of cornification, and screening of several connexin genes with known cutaneous phenotype, such as those for Cx26, Cx30, Cx30.3, and Cx31, may be required. Connexins are integral membrane proteins forming aqueous gap junction channels that allow the diffusional exchange of ions and small metabolites between cells, thus coordinating metabolic activities in multicellular tissues. Dominant mutations in the Cx26 gene GJB2 have been shown to cause keratitis-ichthyosis-deafness (KID) syndrome, palmoplantar keratoderma associated with hearing loss, and Vohwinkel syndrome. Missense mutations in the closely related Cx30 gene GJB6 underlie Clouston syndrome (autosomal dominant hidrotic ectodermal dysplasia). We report a 6-y-old boy with phenotypic characteristics of KID syndrome as well as atrichia. In contrast to other KID syndrome patients, molecular analysis of the connexin gene GJB2 did not disclose a pathogenic mutation, although the patient was homozygous for a common polymorphism (V27I) in the coding sequence of Cx26. Nevertheless, screening of GJB6 revealed a heterozygous missense mutation (V37E) predicted to alter sequence and charge of the first transmembrane helix of Cx30, which was previously implicated in Clouston syndrome (Smith et al, 2002). The presence of a pathogenic Cx30 mutation and the lack of a pathologic molecular change in Cx26 in this patient, whose clinical features predominantly resemble KID syndrome, suggest genetic heterogeneity of KID syndrome and underscore that mutations in Cx30, similar to those in Cx26 or Cx31, can cause different phenotypes. Based on our results, connexin gene mutations should be considered in patients presenting with congenital sensorineural hearing loss and disorders of cornification, and screening of several connexin genes with known cutaneous phenotype, such as those for Cx26, Cx30, Cx30.3, and Cx31, may be required. Keratitis-ichthyosis-deafness (KID) syndrome (OMIM 148210) and Clouston syndrome (hidrotic ectodermal dysplasia; OMIM 129500) are rare autosomal dominant ectodermal dysplasias due to germline mutations in the connexin genes GJB2 and GJB6, respectively, which cluster at chromosome 13q11 and encode the closely related gap junction proteins Cx26 and Cx30 (Lamartine et al., 2000Lamartine J. Munhoz Essenfelder G. Kibar Z. et al.Mutations in GJB6 cause hidrotic ectodermal dysplasia.Nat Genet. 2000; 26: 142-144https://doi.org/10.1038/79851Crossref PubMed Scopus (206) 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). KID and Clouston syndrome share a few overlapping features, such as nail dystrophy, hair loss, and palmoplantar keratoderma. Although the disorders are usually readily distinguishable on clinical grounds in patients with a full-blown picture, the differentiation can be challenging in others. KID syndrome is a rare, mostly sporadic disorder with a broad spectrum of cutaneous features, including erythrokeratoderma, follicular hyperkeratoses, psoriasiform or verrucous plaques, acanthosis, and palmoplantar keratoderma (PPK) often described as reticulated or pitted (reviewed inCaceres-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;Sundaram et al., 2003Sundaram S. Willoughby C. Itin P. Ryynaenen M. Lewanda A. Sybert V.P. Richard G. The clinical spectrum of Keratitis-Ichthyosis-Deafness syndrome.J Invest Dermatol. 2003; 121: A660Google Scholar). Between 90% and 93% of affected individuals have prelingual sensorineural hearing loss (SNHL) (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;Sundaram et al., 2003Sundaram S. Willoughby C. Itin P. Ryynaenen M. Lewanda A. Sybert V.P. Richard G. The clinical spectrum of Keratitis-Ichthyosis-Deafness syndrome.J Invest Dermatol. 2003; 121: A660Google Scholar), which is often bilateral and severe to profound (Sybert, 1997Sybert V.P. Keratitis-Ichthyosis-Deafness syndrome.in: Sybert V.P. Genetic Skin Disorders. Oxford University Press, New York1997: 115-118Google Scholar;Szymko-Bennett et al., 2002Szymko-Bennett Y.M. Russell L.J. Bale S.J. Griffith A.J. Auditory manifestations of Keratitis-Ichthyosis-Deafness (KID) syndrome.Laryngoscope. 2002; 112: 272-280https://doi.org/10.1097/00005537-200202000-00014Crossref PubMed Scopus (32) Google Scholar). Corneal symptoms often manifest during childhood with photophobia, punctate keratitis, and progressive corneal vascularization that may later result in visual decline and blindness (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). Many KID syndrome patients were reported to have sparse or lusterless hair, but only approximately 10%–23% have congenital absence of hair (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;Sundaram et al., 2003Sundaram S. Willoughby C. Itin P. Ryynaenen M. Lewanda A. Sybert V.P. Richard G. The clinical spectrum of Keratitis-Ichthyosis-Deafness syndrome.J Invest Dermatol. 2003; 121: A660Google Scholar). Other findings that are variably present include nail dystrophy, dental anomalies, hypohidrosis, growth delay, increased susceptibility to cutaneous infections, and a propensity for developing squamous cell carcinomas (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). KID syndrome is caused by autosomal dominant missense mutations in the connexin gene GJB2. A common mutation that has been reported in 12 of 15 unrelated patients tested results in the replacement of aspartic acid 50 with asparagine (D50N) in the first extracellular loop of Cx26 (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 Geel et al., 2002van Geel M. van Steensel M.A. Kuster W. Hennies H.C. Happle R. Steijlen P.M. Konig A. HID and KID syndromes are associated with the same connexin 26 mutation.Br J Dermatol. 2002; 146: 938-942https://doi.org/10.1046/j.1365-2133.2002.04893.xCrossref PubMed Scopus (96) 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;Alvarez et al., 2003Alvarez A. Del Castillo I. Pera A. et al.De novo mutation in the gene encoding connexin-26 (GJB2) in a sporadic case of keratitis-ichthyosis-deafness (KID) syndrome.Am J Med Genet. 2003; 117A: 89-91https://doi.org/10.1002/ajmg.a.10851Crossref PubMed Scopus (30) Google Scholar;Yotsumoto et al., 2003Yotsumoto S. Hashiguchi T. Chen X. et al.Novel mutations in GJB2 encoding connexin-26 in Japanese patients with keratitis-ichthyosis-deafness syndrome.Br J Dermatol. 2003; 148: 649-653https://doi.org/10.1046/j.1365-2133.2003.05245.xCrossref PubMed Scopus (67) Google Scholar). This sequence motif is highly conserved among all connexins and any change in composition and charge is likely detrimental for the formation and function of gap junction channels (Rubin et al., 1992Rubin J.B. Verselis V.K. Bennett M.V. Bargiello T.A. Molecular analysis of voltage dependence of heterotypic gap junctions formed by connexins 26 and 32.Biophys J. 1992; 62: 183-193Abstract Full Text PDF PubMed Scopus (86) Google Scholar;White et al., 1995White T.W. Bruzzone R. Paul D.L. The connexin family of intercellular channel forming proteins.Kidney Int. 1995; 48: 1148-1157Crossref PubMed Scopus (104) Google Scholar). Other mutations cluster in the intracellular amino terminus of this gap junction protein (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). Clouston syndrome is an autosomal dominant ectodermal dysplasia particularly common among the French–Canadian population due to a founder effect (Lamartine et al., 2000Lamartine J. Munhoz Essenfelder G. Kibar Z. et al.Mutations in GJB6 cause hidrotic ectodermal dysplasia.Nat Genet. 2000; 26: 142-144https://doi.org/10.1038/79851Crossref PubMed Scopus (206) Google Scholar). The principal features include nail dystrophy, hair loss, and PPK. Nail abnormalities are usually present in all patients and may range from almost normal appearing nails to micro- or anonychia (Clouston, 1929Clouston H.R. A hereditary ectodermal dystrophy.Can Med Assoc J. 1929; 21: 18-31PubMed Google Scholar). Nail plate changes may include thickening, brittleness, discoloration, splitting, and onycholysis (Clouston, 1929Clouston H.R. A hereditary ectodermal dystrophy.Can Med Assoc J. 1929; 21: 18-31PubMed Google Scholar;Clouston, 1939Clouston H.R. The major forms of hereditary ectodermal dysplasia.Can Med Assoc J. 1939; 40: 1-7PubMed Google Scholar;Rajagopalan and Tay, 1977Rajagopalan K. Tay C.H. Hidrotic ectodermal dysplasia: Study of a large Chinese pedigree.Arch Dermatol. 1977; 113: 481-485https://doi.org/10.1001/archderm.113.4.481Crossref PubMed Google Scholar;Hassed et al., 1996Hassed S.J. Kincannon J.M. Arnold G.L. Clouston syndrome: An ectodermal dysplasia without significant dental findings.Am J Med Genet. 1996; 61: 274-276https://doi.org/10.1002/(SICI)1096-8628(19960122)61:3 3.3.CO;2-HCrossref PubMed Google Scholar). Paronychia and nail infections are common (Clouston, 1929Clouston H.R. A hereditary ectodermal dystrophy.Can Med Assoc J. 1929; 21: 18-31PubMed Google Scholar;Kibar et al., 1996Kibar Z. Der Kaloustian V.M. Brais B. Hani V. Fraser F.C. Rouleau G.A. The gene responsible for Clouston hidrotic ectodermal dysplasia maps to the pericentromeric region of chromosome 13q.Hum Mol Genet. 1996; 5: 543-547https://doi.org/10.1093/hmg/5.4.543Crossref PubMed Scopus (48) Google Scholar). Hair abnormalities manifest at birth or later as atrichia or hypotrichosis with brittle, slow-growing hair, and may be progressive. Some but not all patients develop diffuse PPK and discrete hyperpigmentations over joints, whereas strabismus and cataracts are rare (Clouston, 1929Clouston H.R. A hereditary ectodermal dystrophy.Can Med Assoc J. 1929; 21: 18-31PubMed Google Scholar;Clouston, 1939Clouston H.R. The major forms of hereditary ectodermal dysplasia.Can Med Assoc J. 1939; 40: 1-7PubMed Google Scholar;Hazen et al., 1980Hazen P.G. Zamora I. Bruner W.E. Muir W.A. Premature cataracts in a family with hidrotic ectodermal dysplasia.Arch Dermatol. 1980; 116: 1385-1387https://doi.org/10.1001/archderm.116.12.1385Crossref PubMed Scopus (6) Google Scholar). Sweat function and teeth are normal (Rajagopalan and Tay, 1977Rajagopalan K. Tay C.H. Hidrotic ectodermal dysplasia: Study of a large Chinese pedigree.Arch Dermatol. 1977; 113: 481-485https://doi.org/10.1001/archderm.113.4.481Crossref PubMed Google Scholar;Hassed et al., 1996Hassed S.J. Kincannon J.M. Arnold G.L. Clouston syndrome: An ectodermal dysplasia without significant dental findings.Am J Med Genet. 1996; 61: 274-276https://doi.org/10.1002/(SICI)1096-8628(19960122)61:3 3.3.CO;2-HCrossref PubMed Google Scholar;Sybert, 1997Sybert V.P. Keratitis-Ichthyosis-Deafness syndrome.in: Sybert V.P. Genetic Skin Disorders. Oxford University Press, New York1997: 115-118Google Scholar). Unlike in KID syndrome, patients with Clouston syndrome lack vascularizing keratitis and SNHL. The latter has only been described in families with autosomal recessive onychodystrophy (Feinmesser and Zelig, 1961Feinmesser M. Zelig S. Congenital deafness associated with onychodystrophy.Arch Otolaryngol. 1961; 74: 507-508Crossref PubMed Scopus (40) Google Scholar) or autosomal dominant onychodystrophy with additional abnormalities (conical teeth, hypodontia, syndactyly, and polydactyly) without PPK and hair involvement, suggestive of a distinct syndrome (see OMIM 124480) (Robinson et al., 1962Robinson G.C. Miller J.R. Bensimon J.R. Familial ectodermal dysplasia with sensori-neural deafness and other anomalies.Pediatrics. 1962; 30: 797-802Google Scholar).Lamartine et al., 2000Lamartine J. Munhoz Essenfelder G. Kibar Z. et al.Mutations in GJB6 cause hidrotic ectodermal dysplasia.Nat Genet. 2000; 26: 142-144https://doi.org/10.1038/79851Crossref PubMed Scopus (206) Google Scholar identified two different missense mutations in the Cx30 gene, G11R and A88V, each of which segregated with Clouston syndrome in 12 families of French–Canadian and other backgrounds. In addition, a de novo mutation in the first transmembrane domain of Cx30, V37E, has been detected in a patient with sporadic Clouston syndrome (Smith et al., 2002Smith F.J. Morley S.M. McLean W.H. A novel connexin 30 mutation in Clouston syndrome.J Invest Dermatol. 2002; 118: 530-532https://doi.org/10.1046/j.0022-202x.2001.01689.xCrossref PubMed Scopus (79) Google Scholar). Here, we report a young boy with features of KID syndrome and congenital atrichia, who was found to carry a deleterious missense mutation in the Cx30 gene (GJB6). Our findings expand the phenotypic spectrum of mutations in GJB6, and further underscore the overlapping nature of syndromes thus far attributed to the four connexins with cutaneous manifestations. The proband is a 6-y-old boy born to non-consanguineous, unaffected parents after an uneventful pregnancy. The maternal family history did not reveal evidence for hearing impairment or ectodermal dysplasia. The paternal family history could not be obtained. Since birth, he has had dry, leathery skin; short and thickened dystrophic nails; no scalp hair, eyebrows and eyelashes; and severe photophobia. His sweating has been impaired, which was confirmed with a bromophenol test at 6.5 mo of age. In early childhood, his growth and weight remained below the 5th percentile and his motor development was slightly delayed. In recent years, he has caught up to the 5th-10th percentile for these growth parameters. Audiological testing revealed prelingual bilateral mild to moderate SNHL but his speech has improved significantly with the use of hearing aids since the age of 5 y. Mild keratitis and corneal vascularization were evident on ophthalmologic examination at the age of 5 y. At 6.5 mo of age, dermatological examination revealed generalized erythema and thickened skin with a cobblestone appearance, sparing only the diaper area. In addition, a verrucous, hyperkeratotic plaque on his left antecubital fossa was noted. Six years later Figure 1, the patient's skin continued to show slight erythroderma and was covered with innumerable spiny papules with accentuation on the posterior neck, lower back, knees, and elbows. Only the glans penis and sandal strap regions of the dorsal feet were spared. He also had diffuse PPK with a cobblestone or ceribriform surface. In addition, a few scattered, verrucous, and fissured papules up to 10 mm in diameter were noted in the perineal area. The patient had complete absence of body and scalp hair, eyebrows, and eyelashes. He had mild conjunctival injection and corneal neovascularization, but no blepharitis, ectropion, eyelid adhesions, or nystagmus. His primary teeth were normal in number and shape, although he had a few dental cavities. The oral mucosa was unremarkable. Several of his fingernails had been shed, and the remaining ones, similar to the toenails, were thickened, short, and demonstrated distal onycholysis. He had mild heat intolerance during the summer months. The past medical history also revealed recurrent episodes of nail infections as well as an unrelated peanut allergy. At 6.5 mo of age, a skin biopsy of the patient's left posterior arm revealed an abundance of eccrine sweat glands and ducts, which could be age-related, whereas only a few small, abortive hair follicles without hair shafts were identified Figure 1. The ostia of appendages showed dilatation and plugging with orthokeratotic hyperkeratosis and a prominent granular layer. Sebaceous glands were present. The presence of all key features of KID-syndrome prompted initial mutation analysis of the GJB2 (Cx26) gene. The proband was found to be homozygous for a G to A transition at nucleotide 79 (from ATG start site) in codon 27, changing a hydrophobic residue, valine (GTC), with another, isoleucine (ATC) (V27I). This substitution, also found in unaffected controls in homozygous or heterozygous state, represents a common polymorphism with a frequency of the minor (A) allele of 0.005–0.52 in different populations (Kelley et al., 1998Kelley P.M. Harris D.J. Comer B.C. Askew J.W. Fowler T. Smith S.D. Kimberling W.J. Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss.Am J Hum Genet. 1998; 62: 792-799https://doi.org/10.1086/301807Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar;Abe et al., 2000Abe S. Usami S. Shinkawa H. Kelley P.M. Kimberling W.J. Prevalent connexin 26 gene (GJB2) mutations in Japanese.J Med Genet. 2000; 37: 41-43https://doi.org/10.1136/jmg.37.1.41Crossref PubMed Scopus (318) Google Scholar;Kudo et al., 2000Kudo T. Ikeda K. Kure S. et al.Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population.Am J Med Genet. 2000; 90: 141-145https://doi.org/10.1002/(SICI)1096-8628(20000117)90:2 3.0.CO;2-GCrossref PubMed Scopus (176) Google Scholar;Park et al., 2000Park H.J. Hahn S.H. Chun Y.M. Park K. Kim H.N. Connexin26 mutations associated with nonsyndromic hearing loss.Laryngoscope. 2000; 110: 1535-1538https://doi.org/10.1097/00005537-200009000-00023Crossref PubMed Scopus (171) Google Scholar). In our Northern European control cohort (156 chromosomes), the allele frequency was 0.013. Since no other sequence variants were detected in GJB2, the connexin genes GJB6 as well as GJB3, GJB4, GJB5, and GJA1 were scrutinized. The proband harbored a heterozygous 110T→A transversion in GJB6, which was not present in his mother's DNA sample Figure 2. His father was unavailable for testing. This point mutation is predicted to lead to a non-conservative replacement of valine 37 (GTG) with a negatively charged glutamic acid (GAG) (V37E) in the first transmembrane helix of Cx30. The nucleotide change was not detected in a cohort of 50 unrelated individuals of Northern European origin without genodermatoses or hearing loss, nor in the additional 100 Northern European controls published previously (Smith et al., 2002Smith F.J. Morley S.M. McLean W.H. A novel connexin 30 mutation in Clouston syndrome.J Invest Dermatol. 2002; 118: 530-532https://doi.org/10.1046/j.0022-202x.2001.01689.xCrossref PubMed Scopus (79) Google Scholar), excluding the possibility that V37E represents a non-consequential sequence polymorphism. No sequence aberrations were found in four other connexin genes expressed in stratifying epithelia of ectodermal origin, including GJB3, GJB4, GJB5, and GJA1. Connexins are a large family of small integral membrane proteins utilized by most vertebrate tissues to establish direct cell–cell communication through gap junction channels. Similar to certain other adhesion molecules, such as claudins, occludin, or PMP22, they contain four hydrophobic domains transversing the plasma membrane (M1–M4, Figure 2). These α-helices separate 2 highly conserved hydrophilic loops extending into the extracellular space from 3 relatively variable cytoplasmic domains. Six connexin molecules oligomerize into homomeric or heteromeric connexin hemichannels, which are integrated into the plasma membrane where they may accumulate to gap junction plaques and associate with their counterparts in adjacent cells to complete intercellular channels. These channels permit the diffusion of small molecules (up to ∼1 kDa) between cells and mediate the exchange of signals and nutrients, thereby coordinating cellular activities and response to stimuli. In the skin, up to 10 different connexin molecules have been detected, which are expressed in spatial and temporal overlapping patterns, and are partially shared by other stratified epithelia (Richard, 2000aRichard G. Connexins: A connection with the skin.Exp Dermatol. 2000; 9: 77-96https://doi.org/10.1034/j.1600-0625.2000.009002077.xCrossref PubMed Scopus (136) Google Scholar;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). Despite the apparent redundancy of the gap junction system, each connexin appears to have specific properties, which is illustrated by the fact that inherited defects in several connexin genes result in related yet distinct skin disorders, including PPK associated with SNHL, Vohwinkel syndrome and KID syndrome (GJB2), Clouston syndrome (GJB6), and erythrokeratodermia variabilis (GJB3 and GJB4) (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). We report a patient with an unusual clinical presentation resulting in diagnostic difficulties. He presented with a combination of clinical features characteristic of KID syndrome, including congenital bilateral SNHL, keratitis, and mild erythroderma. In addition, he had congenital absence of hair, PPK, and nail dystrophy, which are also seen in Clouston syndrome, and generalized spiny hyperkeratotic papules as described in HID syndrome (Hystrix-like Ichthyosis Deafness syndrome) (Traupe, 1989Traupe H. The Ichthyoses.A Guide to Clinical Diagnosis, Genetic Counseling, and Therapy. 1st edn. Springer Verlag, Berlin-Heidelberg-New York1989: 192-197Crossref Google Scholar). In contrast to all other KID and HID syndrome, patients harboring pathogenic mutations in GJB2 (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 Geel et al., 2002van Geel M. van Steensel M.A. Kuster W. Hennies H.C. Happle R. Steijlen P.M. Konig A. HID and KID syndromes are associated with the same connexin 26 mutation.Br J Dermatol. 2002; 146: 938-942https://doi.org/10.1046/j.1365-2133.2002.04893.xCrossref PubMed Scopus (96) 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), our molecular studies revealed a heterozygous mutation in GJB6. The identified mutation V37E in GJB6 was recently observed in a patient with Clouston syndrome without evidence for abnormal sweating, hearing, photophobia, and keratitis (Smith et al., 2002Smith F.J. Morley S.M. McLean W.H. A novel connexin 30 mutation in Clouston syndrome.J Invest Dermatol. 2002; 118: 530-532https://doi.org/10.1046/j.0022-202x.2001.01689.xCrossref PubMed Scopus (79) Google Scholar). These findings illustrate a perplexing phenotypic variability of the GJB6 mutation V37E and underscore the profound influence of genetic and epigenetic factors that modify the clinical phenotype. In fact, other GJB6 mutations originally described in patients with Clouston syndrome, such as G11R and A88V, may also result in forme fruste with hypertrophic nail dystrophy closely resembling pachyonychia congenita, alone or in combination with hypotrichosis (van Steensel et al., 2003van Steensel M.A.M. Jonkman M.F. van Geel M. Steijlen P.M. McLean I.W.H. Smith F.J.D. Clouston syndrome can mimic pachyonychia congenita.J Invest Dermatol. 2003; 121: 1035-1038https://doi.org/10.1046/j.1523-1747.2003.12527.xAbstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). In contrast, mutation T5M has been associated with SNHL without any other associated features (Grifa et al., 1999Grifa A. Wagner C.A. D'Ambrosio L. et al.Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus.Nat Genet. 1999; 23: 16-18Crossref PubMed Scopus (309) Google Scholar). It is tempting to speculate that the unique disorder of the patient studied here might be related, at least in part, to the presence of a homozygous sequence polymorphism in GJB2 replacing valine27 with isoleucine. Despite detailed functional analyses of numerous recessive and dominant Cx26 mutations, the functional properties of this particular polymorphic variant of Cx26 remain unknown. Other Cx26 mutations that were originally considered non-consequential polymorphisms, such as M34T and V37I (orthologous to the GJB6 mutation reported here), were subsequently found to represent recessive alleles with reduced or absent channel permeability (Bruzzone et al., 2003Bruzzone R. Veronesi V. Gomes D. et al.Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness.FEBS Lett. 2003; 533: 79-88Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar;Oshima et al., 2003Oshima A. Doi T. Mitsuoka K. Maeda S. Fujiyoshi Y. Roles of M34, C64, and R75 in the assembly of human connexin 26: Implication for key amino acid residues for channel formation and function.J Biol Chem. 2003; 278: 1807-1816https://doi.org/10.1074/jbc.M207713200Crossref PubMed Scopus (86) Google Scholar). Hence, it will be interesting to learn if V27I-Cx26 has consequences on Cx26 function and, perhaps, on assembly or channel properties of mixed channels formed with wild-type Cx30 or mutant V37E-Cx30, which could aggravate the pathological processes. Our findings demonstrate for the first time that KID syndrome is genetically heterogeneous and caused by mutations in either GJB2 or GJB6. Therefore, KID syndrome is another example of a connexin disorder attributable to mutations in more than one connexin gene, as are EKV (GJB3, GJB4), non-syndromic SNHL (GJB2, GJB6, GJB3), or cataract (GJA3, GJA8). Although dominant Cx26 mutations in KID syndrome either affect a hypermutable CpG dinucleotide in the first extracellular domain or cluster in the N-terminus, t
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