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Novel Mutations in the Connexin Gene GJB4 (Cx30.3) and GenotypePhenotype Correlations

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Novel Mutations in the Connexin Gene GJB4 (Cx30.3) and Genotype�Phenotype Correlations ORIGINAL ARTICLE Genetic Heterogeneity in Erythrokeratodermia Variabilis: Novel Mutations in the Connexin Gene GJB4 (Cx30.3) and GenotypeÀPhenotype Correlations Gabriele Richard, Nkecha Brown, Fatima Rouan, Jan-Gerrit Van der Schroe¡,n Emilia Bijlsma,w Lawrence F. Eichen¢eld,zVirginia P. Sybert,y Kenneth E. Greer,z Peter Hogan,nn Carmen Campanelli, John G. Compton,ww Sherri J. Bale,ww John J. DiGiovanna,yy and Jouni Uitto Department of Dermatology and Cutaneous Biology, Je¡erson Medical College, and Je¡erson Institute of Molecular Medicine,Thomas Je¡erson University, Philadelphia, Pennsylvania, U.S.A.; nDepartments of Dermatology, Bronovo Hospital, Red Cross Hospital, and Juliana Children’s Hospital,The Hague,The Netherlands; wDepartment of Genetics, University of Amsterdam,The Netherlands; zDepartment of Pediatric Dermatology, University of California San Diego and Children’s Hospital, San Diego, California, U.S.A.; yDivision of Dermatology, Department of Medicine, University of Washington, Seattle,Washington, U.S.A.; zDepartment of Dermatology, University of Virginia Medical Center, Charlottesville,Virginia, U.S.A.; nnChildren’s Hospital at Westmead, Australia; yyDepartment of Dermatology, Brown University/Rhode Island Hospital, Providence, Rhode Island, and NCI, NIH, Bethesda, Maryland, U.S.A.; wwGenetic Studies Section, NIAMS, NIH, Bethesda, MD/GeneDx, Rockville, Maryland, U.S.A. Erythrokeratodermia variabilis is an autosomal domi- unrelated families harbored point mutations leading to nant genodermatosis characterized by persistent amino acid substitution F137L, which was also reported plaque-like or generalized hyperkeratosis and transient in GJB3, yet the extent and severity of hyperkeratosis red patches of variable size, shape, and location.The was milder compared to the corresponding mutation disorder maps to a cluster of connexin genes on chro- in GJB3.Two mutations (T85P, F137L) were associated mosome 1p34^p35.1 and, in a subset of families, results with the occurrence of rapidly changing erythematous from mutations in the gene GJB3 encoding the gap patches with prominent, circinate, or gyrate borders in junction protein connexin-31 (Cx31).A recent report a¡ected children but not in adults, supporting the no- suggested the involvement of another connexin gene tion that this feature is speci¢c to Cx30.3 defects. Never- (GJB4) in the etiology of erythrokeratodermia variabi- theless, we observed highly variable intrafamilial lis.In this study, we sequenced the coding region of phenotypes, suggesting the strong in£uence of modify- GJB4 in 13 unrelated erythrokeratodermia variabilis fa- ing genetic and epigenetic factors.In addition to patho- milies without detectable mutations in GJB3.Mutation genic mutations, we identi¢ed several missense analysis revealed six distinct missense mutations in ¢ve mutations and a 4 bp deletion within the GJB4 coding families and a sporadic case of erythrokeratodermia region, which might represent either inconsequential variabilis, all of which were not found in controls.Mu- polymorphisms or recessive mutations.In conclusion, tation G12D, identi¢ed in an extended Dutch family, our results demonstrate genetic heterogeneity in ery- lies in the predicted amino-terminus and may interfere throkeratodermia variabilis, and emphasize that inter- with the £exibility of this domain, connexin selectivity, cellular communication mediated by both Cx31 and or gating polarity of gap junction channels.Other mu- Cx30.3 is crucial for epidermal di¡erentiation. Key tations (R22H, T85P, F137L, F189Y) were located in the words: connexin/epidermal di¡erentiation/erythrokeratodermia transmembrane domains of Cx30.3, and are predicted variabilis/gap junction communication/mutation. J Invest to hinder regulation of voltage gating or alter the ki- Dermatol 120:601 ^609, 2003 netics of channel closure.A¡ected individuals of two n 1925, Dutch dermatologist Mendes da Costa described the extraordinarily variable areas of transient erythema that may co- striking clinical features of a genodermatosis, which he exist or occur independently. Some patients develop relatively named ‘‘erythro- et keratodermia variabilis’’ (EKV; MIM ¢xed, yellow- or red-brown, hyperkeratotic plaques with well- 133200) (Mendes da Costa, 1925). As re£ected by this name, demarcated, geographic borders that are symmetrically distribu- EKVis characterized by the presence of hyperkeratosis and ted over the extensor surface of extremities, buttocks, and lateral I trunk. In others, hyperkeratosis is persistently severe and wide- spread, with accentuated skin markings, ¢ne attached scaling, Manuscript received November 25, 2002; revised December 16, 2002; ac- and, rarely, ichthyosis hystrix-like appearance. Patchy or di¡use cepted for publication December 19, 2002 4 Reprint requests to: Gabriele Richard, Department of Dermatology and palmoplantar keratoderma (PPK) is common ( 50%), and areas Cutaneous Biology, Thomas Je¡erson University, 233 S 10th St, BLSB, of super¢cial peeling or hypertrichosis are not unusual (Richard, Suite 409, Philadelphia, PA 19107. Email: [email protected] 2001). The hallmark of EKVis the continual occurrence of Abbreviations: Cx, connexin; EKV, erythrokeratodermia variabilis; NT, transient, sharply outlined, ¢gurate red patches of variable amino-terminus; PPK, palmoplantar keratoderma. intensity that fade within a few hours or days. The erythema 0022-202X/03/$15.00 . Copyright r 2003 by The Society for Investigative Dermatology, Inc. 601 602 RICHARD ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY is often triggered by sudden temperature changes or unrelated EKVfamilies that did not harbor detectable mutations emotional stress, whereas hyperkeratosis may be provoked in the Cx31 gene GJB3. by chronic mechanical irritation of the skin (Richard, 2001). EKVis inherited as an autosomal dominant trait and has been MATERIALS AND METHODS mapped in several extended families to a single genetic locus on human chromosome 1p34Àp35.1 (van der Schroe¡ et al, 1984; Patients and biologic material We studied 57 patients a¡ected with Richard et al, 1997; Macari et al, 2000). The 2.6 cM candidate gene EKVfrom 13 unrelated families with their informed consent (108 region was found to harbor four connexin (Cx) genes encoding individuals in total). Our cohort comprised ¢ve multigeneration families the gap junction proteins Cx30.3 (GJB4), Cx31 (GJB3), Cx31.1 demonstrating linkage to the 1p locus (EKV1À5) (Richard et al, 1997; (GJB5), and Cx37 (GJA4) (Richard et al, 1997; Macari et al,2000), S. Morley, personal communication), four nuclear families (EKV6À9), which cluster within less than 40 kb. In 1998, Richard et al iden- and four sporadic cases (EKV10À13). With the exception of an African- American child, other patients were of northern and central European ti¢ed the GJB3 gene and detected pathogenic missense mutations origin. The clinical diagnosis of EKVwas established in at least one in four families with EKV, linking for the ¢rst time a defect in a¡ected individual in each family by medical history, dermatologic the cutaneous gap junction system to disturbed epidermal di¡er- examination performed by at least two dermatologists, and histo- entiation and function (Richard et al, 1998a).To date, a total of six pathologic evaluation of a skin biopsy. DNA samples from all partici- distinct dominant GJB3 mutations have been identi¢ed in eight pating individuals were obtained either from venous blood samples using unrelated EKVfamilies (Wilgoss et al, 1999; Richard et al,2000). standard extraction procedures or from buccal mucosa cells (Richards et al, All nucleotide changes lead to heterozygous amino acid substitu- 1993). tions, four of which (G12D, G12R, R42P, and C86S) were shown to alter gap junction communication and/or induce cell death DNA ampli¢cation and mutation analysis The genomic sequence of GJB4 was obtained from the published sequence of human clone in vitro (Di et al, 2002; Diestel et al, 2002; Rouan et al, in press). In RP1^34M23 assigned to chromosome 1p34.3^36.11 (GenBank accession addition, evidence emerged for an autosomal recessive variant number AL121988.10), which contains a contiguous cluster of four of EKVcaused by the homozygous missense mutation L34P connexin genes including GJA4, GJB3, GJB4,andGJB5. The genomic (Gottfried et al, 2002). Nevertheless, as more than half of all tested organization of GJB4 is similar to other connexin genes, including a ¢rst EKVfamilies did not harbor GJB3 mutations, it was proposed untranslated exon and a second exon that contains the entire coding that EKVmight be genetically heterogeneous (Richard et al, information, separated by a single intron. For mutation analysis, using 2000). This hypothesis was supported by genetic studies in a large polymerase chain reaction (PCR) we ampli¢ed exon 2 and £anking untranslated regions in a 965 bp fragment using primers (1 þ) Israeli-Kurdish EKVfamily, which revealed a heterozygous mis- 0 0 0 sense mutation (F137L) in the gene GJB4 encoding Cx30.3, thus 5 -TCAATCGCACCAGCATTAAG-3 and (2À)5-GGGGGACCTGTT GATCTTATC-30 derived from the genomic sequence. PCR ampli¢cation implicating yet another connexin gene in the pathogenesis of was performed from genomic DNA using Taq DNA polymerase (Qiagen, EKV(Macari et al,2000). Valencia, CA) and standard PCR conditions (941C for 2 min; 36 cycles of Both Cx31 and Cx30.3 appear to be preferentially expressed in 941C for 30 s, 601C for 50 s, 721C for 1 min; and ¢nally 721Cfor7min). the upper di¡erentiating
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