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Gabriele Richard - One of the best experts on this subject based on the ideXlab platform.
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Divergent effects of two sequence variants of GJB3 (G12D and R32W) on the function of connexin 31 in vitro.
Experimental dermatology, 2003Co-Authors: Fatima Rouan, Andrzej Fertala, M. Wahl, M. Jost, Ulrich Rodeck, Jouni Uitto, Gabriele RichardAbstract:Recently, we identified several missense mutations of the connexin gene GJB3 encoding connexin 31 (Cx31) in Erythrokeratodermia variabilis (EKV), an autosomal dominant skin disorder. These mutations include G12D, which replaces a conserved glycine residue in the amino-terminus of Cx31 and is associated with a severe EKV phenotype. In contrast, the biologic relevance of the GJB3 sequence variant R32W located in the first transmembrane domain of Cx31 is disputed. To examine the effects of these sequence variants on Cx31 biogenesis and gap junction activity we expressed wild type and mutant Cx31-Flag constructs in HeLa cells. Using immunostaining, all expression variants were detected in the cytoplasm and in a punctate pattern at the cell surface, indicating that G12D and R32W did not interfere with either protein synthesis or transport to the cell membrane. Similarly, oligomerization into hemichannels appeared not impaired when expressing either Cx31 mutant as assessed by size exclusion chromatography, immunoblotting and immunostaining. However, dye transfer experiments and monitoring of intracellular calcium levels in response to serum stimulation revealed that G12D-Cx31 did not form functional gap junction channels, probably due to incorrect assembly or altered properties of Cx31 channels. In contrast, intercellular coupling between cells expressing R32W-Cx31 was comparable to that of wtCx31, suggesting that R32W is a functionally inconsequential polymorphism of Cx31.
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Genetic heterogeneity in Erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations.
The Journal of investigative dermatology, 2003Co-Authors: Gabriele Richard, Nkecha Brown, Fatima Rouan, Jan Gerrit Van Der Schroeff, Emilia K. Bijlsma, Lawrence F. Eichenfield, Virginia P. Sybert, Kenneth E. Greer, Peter Hogan, Carmen CampanelliAbstract:Erythrokeratodermia variabilis is an autosomal dominant genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location. The disorder maps to a cluster of connexin genes on chromosome 1p34-p35.1 and, in a subset of families, results from mutations in the gene GJB3 encoding the gap junction protein connexin-31 (Cx31). A recent report suggested the involvement of another connexin gene (GJB4) in the etiology of Erythrokeratodermia variabilis. In this study, we sequenced the coding region of GJB4 in 13 unrelated Erythrokeratodermia variabilis families without detectable mutations in GJB3. Mutation analysis revealed six distinct missense mutations in five families and a sporadic case of Erythrokeratodermia variabilis, all of which were not found in controls. Mutation G12D, identified in an extended Dutch family, lies in the predicted amino-terminus and may interfere with the flexibility of this domain, connexin selectivity, or gating polarity of gap junction channels. Other mutations (R22H, T85P, F137L, F189Y) were located in the transmembrane domains of Cx30.3, and are predicted to hinder regulation of voltage gating or alter the kinetics of channel closure. Affected individuals of two unrelated families harbored point mutations leading to amino acid substitution F137L, which was also reported in GJB3, yet the extent and severity of hyperkeratosis was milder compared to the corresponding mutation in GJB3. Two mutations (T85P, F137L) were associated with the occurrence of rapidly changing erythematous patches with prominent, circinate, or gyrate borders in affected children but not in adults, supporting the notion that this feature is specific to Cx30.3 defects. Nevertheless, we observed highly variable intrafamilial phenotypes, suggesting the strong influence of modifying genetic and epigenetic factors. In addition to pathogenic mutations, we identified several missense mutations and a 4 bp deletion within the GJB4 coding region, which might represent either inconsequential polymorphisms or recessive mutations. In conclusion, our results demonstrate genetic heterogeneity in Erythrokeratodermia variabilis, and emphasize that intercellular communication mediated by both Cx31 and Cx30.3 is crucial for epidermal differentiation.
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Expression of a connexin31 mutation causing Erythrokeratodermia variabilis is lethal for HeLa cells.
Biochemical and biophysical research communications, 2002Co-Authors: Simone Diestel, Gabriele Richard, Britta Döring, Otto TraubAbstract:Abstract The autosomal dominant skin disorder Erythrokeratodermia variabilis (EKV) has been linked to mutations in the human connexin31 (hCx31) gene, which is expressed in the epidermis. We characterized and compared a pathogenic mutation resulting in replacement of amino acid glycine 12 with arginine (G12R) with wild-type hCx31 protein. HeLa cells were transfected with wild-type and mutant hCx31 cDNA, respectively, using different—constitutive and inducible—vector systems. Independent of the expression vector, wild-type and mutant hCx31 were expressed at comparative levels and localized at the plasma membranes. Mutated channels (hCx31G12R) showed higher conductance in dye coupling studies than wild type channels. Furthermore, HeLa cells died within 5 days after constitutive expression of the mutant protein. Using an inducible expression system, we demonstrated a direct correlation between survival/life span of transfected HeLa cells and expression level of the mutant protein, indicating a gain-of-function mechanism due to a defective channel closure mechanism.
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The spectrum of mutations in Erythrokeratodermias--novel and de novo mutations in GJB3.
Human genetics, 2000Co-Authors: Gabriele Richard, Nkecha Brown, Lisa E. Smith, Sherri J. Bale., A. Terrinoni, G. Melino, R.m. Mackie, Jouni UittoAbstract:Intercellular channels in skin are a complex and functionally diverse system formed by at least eight connexins (Cx). Our recent molecular studies implicating Cx defects in inherited skin disorders emphasize the critical role of this signaling pathway in epidermal differentiation. Erythrokeratodermia variabilis (EKV) is an autosomal dominant genodermatosis with a striking phenotype characterized by the independent occurrence of transient localized erythema and hyperkeratosis. The disease maps to 1p34-p35, and recently we identified the causative gene GJB3 encoding Cx31. We have now investigated GJB3 in two families and three sporadic cases with EKV, and report three new heterozygous mutations. In a sporadic case, we detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexons. In another family, all three affected individuals carried two distinct mutations on the same GJB3 allele. However, only a de novo heterozygous missense mutation replacing arginine 42 with proline (R42P) co-segregated with the disease, while a 12 bp deletion predicted to eliminate four amino acid residues in the variable carboxy terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. Including the previously published mutations, in toto, five different missense mutations have now been detected in 6 out of 17 families investigated by our laboratory, all of which presumably affect the cytoplasmic amino terminal and transmembrane domains of Cx31. In contrast, two mutations linked to progressive high-tone hearing impairment were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. However, the phenotypic spectrum of GJB3 mutations seems not to include progressive symmetric Erythrokeratodermia, another dominant genodermatosis with overlapping features, since no mutations were found in six unrelated families tested.
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Mutations in the human connexin gene GJB3 cause Erythrokeratodermia variabilis
Nature Genetics, 1998Co-Authors: Gabriele Richard, Daniel Hohl, John J Digiovanna, Lisa E. Smith, Regina A. Bailey, Peter Itin, Ervin H. Epstein, John G. Compton, Sherri J. Bale.Abstract:Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability ^ 1 . It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis (Fig. 1). Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p (Refs 2 , 3 ), EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene ( GJA4 ) encoding the gap junction protein α-4 (connexin 31, Cx31) was excluded by sequence analysis ^ 4 . Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes ^ 5 , 6 led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3 , GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.
G. Richard - One of the best experts on this subject based on the ideXlab platform.
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A new, recurrent mutation of GJB3 (Cx31) in Erythrokeratodermia variabilis.
The British journal of dermatology, 2005Co-Authors: S.m. Morley, M.i. White, M. Rogers, D. Wasserman, P. Ratajczak, W.h.i. Mclean, G. RichardAbstract: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 (625CT; 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.
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The spectrum of mutations in Erythrokeratodermias – novel and de novo mutations in GJB3
Human Genetics, 2000Co-Authors: G. Richard, Nkecha Brown, L.e. Smith, A. Terrinoni, G. Melino, R.m. Mackie, S.j. Bale, J. UittoAbstract:Intercellular channels in skin are a complex and functionally diverse system formed by at least eight connexins (Cx). Our recent molecular studies implicating Cx defects in inherited skin disorders emphasize the critical role of this signaling pathway in epidermal differentiation. Erythrokeratodermia variabilis (EKV) is an autosomal dominant genodermatosis with a striking phenotype characterized by the independent occurrence of transient localized erythema and hyperkeratosis. The disease maps to 1p34-p35, and recently we identified the causative gene GJB3 encoding Cx31. We have now investigated GJB3 in two families and three sporadic cases with EKV, and report three new heterozygous mutations. In a sporadic case, we detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexons. In another family, all three affected individuals carried two distinct mutations on the same GJB3 allele. However, only a de novo heterozygous missense mutation replacing arginine 42 with proline (R42P) co-segregated with the disease, while a 12 bp deletion predicted to eliminate four amino acid residues in the variable carboxy terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. Including the previously published mutations, in toto, five different missense mutations have now been detected in 6 out of 17 families investigated by our laboratory, all of which presumably affect the cytoplasmic amino terminal and transmembrane domains of Cx31. In contrast, two mutations linked to progressive high-tone hearing impairment were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. However, the phenotypic spectrum of GJB3 mutations seems not to include progressive symmetric Erythrokeratodermia, another dominant genodermatosis with overlapping features, since no mutations were found in six unrelated families tested.
Nkecha Brown - One of the best experts on this subject based on the ideXlab platform.
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Genetic heterogeneity in Erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations.
The Journal of investigative dermatology, 2003Co-Authors: Gabriele Richard, Nkecha Brown, Fatima Rouan, Jan Gerrit Van Der Schroeff, Emilia K. Bijlsma, Lawrence F. Eichenfield, Virginia P. Sybert, Kenneth E. Greer, Peter Hogan, Carmen CampanelliAbstract:Erythrokeratodermia variabilis is an autosomal dominant genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location. The disorder maps to a cluster of connexin genes on chromosome 1p34-p35.1 and, in a subset of families, results from mutations in the gene GJB3 encoding the gap junction protein connexin-31 (Cx31). A recent report suggested the involvement of another connexin gene (GJB4) in the etiology of Erythrokeratodermia variabilis. In this study, we sequenced the coding region of GJB4 in 13 unrelated Erythrokeratodermia variabilis families without detectable mutations in GJB3. Mutation analysis revealed six distinct missense mutations in five families and a sporadic case of Erythrokeratodermia variabilis, all of which were not found in controls. Mutation G12D, identified in an extended Dutch family, lies in the predicted amino-terminus and may interfere with the flexibility of this domain, connexin selectivity, or gating polarity of gap junction channels. Other mutations (R22H, T85P, F137L, F189Y) were located in the transmembrane domains of Cx30.3, and are predicted to hinder regulation of voltage gating or alter the kinetics of channel closure. Affected individuals of two unrelated families harbored point mutations leading to amino acid substitution F137L, which was also reported in GJB3, yet the extent and severity of hyperkeratosis was milder compared to the corresponding mutation in GJB3. Two mutations (T85P, F137L) were associated with the occurrence of rapidly changing erythematous patches with prominent, circinate, or gyrate borders in affected children but not in adults, supporting the notion that this feature is specific to Cx30.3 defects. Nevertheless, we observed highly variable intrafamilial phenotypes, suggesting the strong influence of modifying genetic and epigenetic factors. In addition to pathogenic mutations, we identified several missense mutations and a 4 bp deletion within the GJB4 coding region, which might represent either inconsequential polymorphisms or recessive mutations. In conclusion, our results demonstrate genetic heterogeneity in Erythrokeratodermia variabilis, and emphasize that intercellular communication mediated by both Cx31 and Cx30.3 is crucial for epidermal differentiation.
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The spectrum of mutations in Erythrokeratodermias--novel and de novo mutations in GJB3.
Human genetics, 2000Co-Authors: Gabriele Richard, Nkecha Brown, Lisa E. Smith, Sherri J. Bale., A. Terrinoni, G. Melino, R.m. Mackie, Jouni UittoAbstract:Intercellular channels in skin are a complex and functionally diverse system formed by at least eight connexins (Cx). Our recent molecular studies implicating Cx defects in inherited skin disorders emphasize the critical role of this signaling pathway in epidermal differentiation. Erythrokeratodermia variabilis (EKV) is an autosomal dominant genodermatosis with a striking phenotype characterized by the independent occurrence of transient localized erythema and hyperkeratosis. The disease maps to 1p34-p35, and recently we identified the causative gene GJB3 encoding Cx31. We have now investigated GJB3 in two families and three sporadic cases with EKV, and report three new heterozygous mutations. In a sporadic case, we detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexons. In another family, all three affected individuals carried two distinct mutations on the same GJB3 allele. However, only a de novo heterozygous missense mutation replacing arginine 42 with proline (R42P) co-segregated with the disease, while a 12 bp deletion predicted to eliminate four amino acid residues in the variable carboxy terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. Including the previously published mutations, in toto, five different missense mutations have now been detected in 6 out of 17 families investigated by our laboratory, all of which presumably affect the cytoplasmic amino terminal and transmembrane domains of Cx31. In contrast, two mutations linked to progressive high-tone hearing impairment were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. However, the phenotypic spectrum of GJB3 mutations seems not to include progressive symmetric Erythrokeratodermia, another dominant genodermatosis with overlapping features, since no mutations were found in six unrelated families tested.
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The spectrum of mutations in Erythrokeratodermias – novel and de novo mutations in GJB3
Human Genetics, 2000Co-Authors: G. Richard, Nkecha Brown, L.e. Smith, A. Terrinoni, G. Melino, R.m. Mackie, S.j. Bale, J. UittoAbstract:Intercellular channels in skin are a complex and functionally diverse system formed by at least eight connexins (Cx). Our recent molecular studies implicating Cx defects in inherited skin disorders emphasize the critical role of this signaling pathway in epidermal differentiation. Erythrokeratodermia variabilis (EKV) is an autosomal dominant genodermatosis with a striking phenotype characterized by the independent occurrence of transient localized erythema and hyperkeratosis. The disease maps to 1p34-p35, and recently we identified the causative gene GJB3 encoding Cx31. We have now investigated GJB3 in two families and three sporadic cases with EKV, and report three new heterozygous mutations. In a sporadic case, we detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexons. In another family, all three affected individuals carried two distinct mutations on the same GJB3 allele. However, only a de novo heterozygous missense mutation replacing arginine 42 with proline (R42P) co-segregated with the disease, while a 12 bp deletion predicted to eliminate four amino acid residues in the variable carboxy terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. Including the previously published mutations, in toto, five different missense mutations have now been detected in 6 out of 17 families investigated by our laboratory, all of which presumably affect the cytoplasmic amino terminal and transmembrane domains of Cx31. In contrast, two mutations linked to progressive high-tone hearing impairment were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. However, the phenotypic spectrum of GJB3 mutations seems not to include progressive symmetric Erythrokeratodermia, another dominant genodermatosis with overlapping features, since no mutations were found in six unrelated families tested.
Frances Burden - One of the best experts on this subject based on the ideXlab platform.
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Sphingolipid dysregulation due to lack of functional KDSR impairs proplatelet formation causing thrombocytopenia.
Haematologica, 2018Co-Authors: Tadbir K. Bariana, Veerle Labarque, Jessica Heremans, Chantal Thys, Mara De Reys, Daniel Greene, Benjamin Jenkins, Luigi Grassi, Denis Seyres, Frances BurdenAbstract:Sphingolipids are fundamental to membrane trafficking, apoptosis, and cell differentiation and proliferation. KDSR or 3-keto-dihydrosphingosine reductase is an essential enzyme for de novo sphingolipid synthesis, and pathogenic mutations in KDSR result in the severe skin disorder Erythrokeratodermia variabilis et progressiva-4. Four of the eight reported cases also had thrombocytopenia but the underlying mechanism has remained unexplored. Here we expand upon the phenotypic spectrum of KDSR deficiency with studies in two siblings with novel compound heterozygous variants associated with thrombocytopenia, anemia, and minimal skin involvement. We report a novel phenotype of progressive juvenile myelofibrosis in the propositus, with spontaneous recovery of anemia and thrombocytopenia in the first decade of life. Examination of bone marrow biopsies showed megakaryocyte hyperproliferation and dysplasia. Megakaryocytes obtained by culture of CD34+ stem cells confirmed hyperproliferation and showed reduced proplatelet formation. The effect of KDSR insufficiency on the sphingolipid profile was unknown, and was explored in vivo and in vitro by a broad metabolomics screen that indicated activation of an in vivo compensatory pathway that leads to normalization of downstream metabolites such as ceramide. Differentiation of propositus-derived induced pluripotent stem cells to megakaryocytes followed by expression of functional KDSR showed correction of the aberrant cellular and biochemical phenotypes, corroborating the critical role of KDSR in proplatelet formation. Finally, Kdsr depletion in zebrafish recapitulated the thrombocytopenia and showed biochemical changes similar to those observed in the affected siblings. These studies support an important role for sphingolipids as regulators of cytoskeletal organization during megakaryopoiesis and proplatelet formation.
Lisa E. Smith - One of the best experts on this subject based on the ideXlab platform.
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The spectrum of mutations in Erythrokeratodermias--novel and de novo mutations in GJB3.
Human genetics, 2000Co-Authors: Gabriele Richard, Nkecha Brown, Lisa E. Smith, Sherri J. Bale., A. Terrinoni, G. Melino, R.m. Mackie, Jouni UittoAbstract:Intercellular channels in skin are a complex and functionally diverse system formed by at least eight connexins (Cx). Our recent molecular studies implicating Cx defects in inherited skin disorders emphasize the critical role of this signaling pathway in epidermal differentiation. Erythrokeratodermia variabilis (EKV) is an autosomal dominant genodermatosis with a striking phenotype characterized by the independent occurrence of transient localized erythema and hyperkeratosis. The disease maps to 1p34-p35, and recently we identified the causative gene GJB3 encoding Cx31. We have now investigated GJB3 in two families and three sporadic cases with EKV, and report three new heterozygous mutations. In a sporadic case, we detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexons. In another family, all three affected individuals carried two distinct mutations on the same GJB3 allele. However, only a de novo heterozygous missense mutation replacing arginine 42 with proline (R42P) co-segregated with the disease, while a 12 bp deletion predicted to eliminate four amino acid residues in the variable carboxy terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. Including the previously published mutations, in toto, five different missense mutations have now been detected in 6 out of 17 families investigated by our laboratory, all of which presumably affect the cytoplasmic amino terminal and transmembrane domains of Cx31. In contrast, two mutations linked to progressive high-tone hearing impairment were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. However, the phenotypic spectrum of GJB3 mutations seems not to include progressive symmetric Erythrokeratodermia, another dominant genodermatosis with overlapping features, since no mutations were found in six unrelated families tested.
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Mutations in the human connexin gene GJB3 cause Erythrokeratodermia variabilis
Nature Genetics, 1998Co-Authors: Gabriele Richard, Daniel Hohl, John J Digiovanna, Lisa E. Smith, Regina A. Bailey, Peter Itin, Ervin H. Epstein, John G. Compton, Sherri J. Bale.Abstract:Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability ^ 1 . It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis (Fig. 1). Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p (Refs 2 , 3 ), EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene ( GJA4 ) encoding the gap junction protein α-4 (connexin 31, Cx31) was excluded by sequence analysis ^ 4 . Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes ^ 5 , 6 led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3 , GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.
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Mutations in the human connexin gene GJB3 cause Erythrokeratodermia variabilis
Nature genetics, 1998Co-Authors: Gabriele Richard, Daniel Hohl, John J Digiovanna, Lisa E. Smith, Regina A. Bailey, Peter Itin, Ervin H. Epstein, John G. Compton, Sherri J. Bale.Abstract:Erythrokeratodermia variabilis (EKV, OMIM 133200) is an autosomal dominant genodermatosis with considerable intra- and interfamilial variability. It has a disfiguring phenotype characterized by the independent occurrence of two morphologic features: transient figurate red patches and localized or generalized hyperkeratosis. Both features can be triggered by external factors such as trauma to the skin. After initial linkage to the RH locus on 1p, EKV was mapped to an interval of 2.6 cM on 1p34-p35, and a candidate gene (GJA4) encoding the gap junction protein alpha-4 (connexin 31, Cx31) was excluded by sequence analysis. Evidence in mouse suggesting that the EKV region harbours a cluster of epidermally expressed connexin genes led us to characterize the human homologues of GJB3 (encoding Cx31) and GJB5 (encoding Cx31.1). GJB3, GJB5 and GJA4 were localized to a 1.1-Mb YAC in the candidate interval. We detected heterozygous missense mutations in GJB3 in four EKV families leading to substitution of a conserved glycine by charged residues (G12R and G12D), or change of a cysteine (C86S). These mutations are predicted to interfere with normal Cx31 structure and function, possibly due to a dominant inhibitory effect. Our results implicate Cx31 in the pathogenesis of EKV, and provide evidence that intercellular communication mediated by Cx31 is crucial for epidermal differentiation and response to external factors.
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Linkage Studies in Erythrokeratodermias: Fine Mapping, Genetic Heterogeneity, and Analysis of Candidate Genes
The Journal of investigative dermatology, 1997Co-Authors: Gabriela Richard, Daniel Hohl, Uwe Wollina, Lisa E. Smith, Peter Itin, Ervin H. Epstein, Jing-ping Lin, Yolanda M. Whyte, Jean-mario Giroux, Lawrence R. CharnasAbstract:Erythrokeratodermias are a clinically heterogeneous group of rare autosomal dominant disorders of cornification with overlapping features including hyperkeratosis and erythema. We ascertained five extended pedigrees with different phenotypes for a linkage study. Three families presented with localized Erythrokeratodermia variabilis, and one with Erythrokeratodermia and ataxia. Another family had Greither disease associated with variable hyperkeratotic plaques. Despite their phenotypic differences, both Erythrokeratodermia variabilis and Erythrokeratodermia with ataxia map to a common region in 1p34–p35. Multipoint linkage and haplotype analyses place Erythrokeratodermia variabilis between the marker D1S496 and D1S186 with a maximum LOD score of 12.88. Our linkage results provide compelling evidence for genetic homogeneity among families of mixed European and French–Canadian origin. In contrast, results excluded Greither's disease from the established Erythrokeratodermia variabilis gene region indicating genetic heterogeneity of Erythrokeratodermias. Based on recombinations, two genes assigned to 1p34–p35 were excluded: cartilage matrix protein and avian myelocytosis viral oncogene. Connexin-37 ( GJA4 ), a member of the connexin gene family, maps within the Erythrokeratodermia variabilis region and is an attractive candidate gene. Direct sequencing of the coding region of GJA4 in four patients revealed several variations, including a novel polymorphism within the 5' cytoplasmic domain, but no pathogenic mutations were found, thus excluding Connexin-37 as a candidate. There is evidence, however, that other epidermally expressed connexins cluster in this region, and one may yet be determined to play a role in the pathogenesis of Erythrokeratodermia variabilis.