Genetic Heterogeneity in Erythrokeratodermia Variabilis: Novel Mutations in the Connexin Gene GJB4 (Cx30.3) and Genotype-Phenotype Correlations Gabriele.

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Genetic Heterogeneity in Erythrokeratodermia Variabilis: Novel Mutations in the Connexin Gene GJB4 (Cx30.3) and Genotype-Phenotype Correlations Gabriele Richard, Nkecha Brown, Fatima Rouan, Carmen Campanelli, Jouni Uitto Journal of Investigative Dermatology Volume 120, Issue 4, Pages 601-609 (April 2003) DOI: 10.1046/j.1523-1747.2003.12080.x Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Mutations G12D in EKV1 and R22H in EKV9. (A) Sequence analysis reveals a G-to-A transition that substitutes glycine 12 with aspartic acid (top left panel) compared to the normal sequence (bottom left panel). Restriction fragment analysis with Tsp45I (lowerright panel) confirms cosegregation of this mutation with the EKV in the family (upper right panel). The mutation introduces a new cut site, resulting in additional DNA bands of 159bp and 51bp (not shown) in affected individuals. M, 100bp marker; U, undigested control; lane numbers correspond to individuals in the pedigree. (B) Variable erythematous patches within well-demarcated, symmetrically distributed hyperkeratotic plaques on the frontal trunk of individual EKV1-5. (C) Pedigree of EKV9 (middle panel) and sequence panels (top left) showing the G-to-A transition replacing arginine 22 with histidine and the normal sequence (bottom left). dHPLC analysis demonstrates an additional peak in the melting curve (EKV9-3) due to heteroduplex formation in the presence of the mutation (top right) compared to a control sample (bottom right). Journal of Investigative Dermatology 2003 120, 601-609DOI: (10.1046/j.1523-1747.2003.12080.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Mutation T85P in EKV2. (A) The sequence chromatogram of affected individual EKV2-5 depicts a heterozygous A-to-C transversion leading to missense mutation T85P in comparison to a control (top panel). This mutation creates a new recognition site for AvaII and results in two additional DNA bands of 210bp and 71bp (not shown) in affected individuals (lower panel). The lane ID numbers correspond to individual ID numbers in the pedigree of EKV2 (middle panel). M, 100bp marker; C, control. (B) Extensive hyperkeratotic plaques on the frontal trunk and arms of an 8-y-old boy (EKV2-30). Note the target-like (→) and circinate (⊳) erythematous patches indicated by arrows. (C) Fixed, hyperkeratotic plaques over both knees without erythema in individual EKV2-13. (D) Preauricular, sharply demarcated erythematous patch occurring during 15min cold exposure of individual EKV2-2. (E) Close-up of erythematous patches with circinate borders in individual EKV2-30. Journal of Investigative Dermatology 2003 120, 601-609DOI: (10.1046/j.1523-1747.2003.12080.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Mutation F189Y in EKV3A. Compared to the wild-type allele, sequence analysis demonstrates a heterozygous T-to-A transversion resulting in missense mutation F189Y (top panel). dHPLC analysis reveales heteroduplex formation (double peak) in a PCR amplicon of individual EKV3-3 (pedigree in middle panel), which is not present in amplicons of the unaffected individual EKV3-11 (single peak, lower panel). (B) Generalized hyperkeratosis with white, attached scale, hypertrichosis, and ridging over the knees with few areas of erythema in individual EKV3-13. Journal of Investigative Dermatology 2003 120, 601-609DOI: (10.1046/j.1523-1747.2003.12080.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Mutations F137L in EKV4 and EKV11. (A), (E) Sequence chromatograms illustrate T-to-C substitution in EKV4 (panel A) and C-to-A substitution in EKV11 (panel E), each of which resides in codon 137 of GJB4 and replaces phenylalanine with leucine (top panels). The presence of transition 409T/C is indicated by a second peak in the dHPLC profile of proband EKV4-3 (A, lower panel). The transversion 411T/A induces a new recognition sequence for MseI, thus creating upon digestion two new DNA bands of 520bp and 67bp (not shown) in the mutant allele (E, lower panel). M, 100bp marker; C, control; U, undigested control; lane numbers correspond to individuals in the pedigree. (B) Figurate outlined, brownish hyperkeratotic plaques with erythematous areas on the abdomen of individual EKV11-6. (C), (D) Acral superficial peeling of the stratum corneum of individuals EKV4-3 and EKV4-6. (F), (G) Symmetrical, sharply demarcated, hyperkeratotic plaques on the legs and buttocks of a 2-y-old boy (EKV11-3). Note the circinate erythema with prominent borders. Journal of Investigative Dermatology 2003 120, 601-609DOI: (10.1046/j.1523-1747.2003.12080.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 A common frameshift polymorphism of GJB4. (A) Sequencing analysis reveals a heterozygous deletion of 4bp (154del4) resulting in frameshift in a control individual without a cutaneous phenotype (left) compared to the wild-type sequence (right). (B) The size difference between the mutant (top) and wild-type (bottom) allele is easily detectable by HPLC under nondenaturing conditions (50°C). Journal of Investigative Dermatology 2003 120, 601-609DOI: (10.1046/j.1523-1747.2003.12080.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Schematic representation of connexin Cx31 and Cx30.3 polypeptides depicting the predicted structural motifs and location of pathogenic mutations in the corresponding genes GJB3 (blue) and GJB4 (red) in EKV. NT, cytoplasmic amino-terminus; M1–M4, transmembrane domains; E1, E2, extracellular domains; CL, cytoplasmic loop; CT, cytoplasmic carboxy-terminus. Domains depicted as black lines are evolutionary conserved, whereas gray lines indicate variable protein domains. Heterozygous dominant mutations in GJB4 (Cx30.3) are shown as filled red circles, whereas mutations in GJB3 (Cx31) are depicted as blue filled circles (Richard, 2001;Richard et al, 1998a;2000;Wilgoss et al, 1999;Macari et al, 2000). The asterisk and shaded background annotate a recessive mutation (Gottfried et al, 2002). Journal of Investigative Dermatology 2003 120, 601-609DOI: (10.1046/j.1523-1747.2003.12080.x) Copyright © 2003 The Society for Investigative Dermatology, Inc Terms and Conditions