A Rare Case of Hypohidrotic Ectodermal Dysplasia Caused by Compound Heterozygous Mutations in the EDAR Gene Yutaka Shimomura, Nobuyuki Sato, Akinori.

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A Rare Case of Hypohidrotic Ectodermal Dysplasia Caused by Compound Heterozygous Mutations in the EDAR Gene Yutaka Shimomura, Nobuyuki Sato, Akinori Miyashita, Tsuyoshi Hashimoto, Masaaki Ito, Ryozo Kuwano Journal of Investigative Dermatology Volume 123, Issue 4, Pages 649-655 (October 2004) DOI: 10.1111/j.0022-202X.2004.23405.x Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Heterozygous exon 2 IVS+1G→A mutation in the patient's EDAR gene. (a) A heterozygous mutation of the splice donor site of intron 2 (exon 2 IVS+1G→A) was identified in the patient's EDAR gene. (b) Haplotype analysis proved maternal and paternal transmission of a chromosomal segment harboring the EDAR locus. The product size of PCR for each micro-satellite marker is indicated. (c) Allele-specific PCR showed that the exon 2 IVS+1G→A mutation exists only in the patient's EDAR gene. MWM, molecular weight markers. GenBank accession numbers for the EDAR exons 1–12: AF130989-AF130996. Journal of Investigative Dermatology 2004 123, 649-655DOI: (10.1111/j.0022-202X.2004.23405.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Heterozygous 1124G→A mutation in the patient's EDAR gene. (a) A heterozygous 1124G→A mutation, which resulted in R375H transition, was identified in exon 12 of the patient's EDAR gene. (b) HhaI restriction enzyme analysis showed that 1124G→A mutation was inherited from the patient's unaffected father. Journal of Investigative Dermatology 2004 123, 649-655DOI: (10.1111/j.0022-202X.2004.23405.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 RT-PCR analysis of the EDAR transcripts. (a) RT-PCR between the EDAR exons 1 and 3 amplified two size variants in the patient. GAPDH mRNA, 597 bp in size, was amplified as a control. (b) Sequence data of the 219 bp fragment in a corresponded to the EDAR transcripts generated by normal splicing. (c) Sequencing of the 150 bp fragment in a revealed aberrant EDAR transcripts with exon 2 skipping, which must have originated from the exon 2 IVS+1G→A mutant allele. (d) RT-PCR, including downstream of the EDAR exon 4, amplified a single fragment whose product sizes were identical between the patient and a control individual. (e) The sequence data of the patient's EDAR exons 1–12 PCR product in d corresponded to the paternal EDAR transcripts generated by normal splicing. A schematic summary of the RT-PCR analysis is also shown below. Note that most of the maternal EDAR mRNA, except for its 5′-end, could not be detected in this study. GenBank accession number for the EDAR cDNA: AF130988. Journal of Investigative Dermatology 2004 123, 649-655DOI: (10.1111/j.0022-202X.2004.23405.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Interaction of wild-type or mutant EDAR with EDARADD. HEK293T cells were co-transfected with a plasmid expressing the N-terminal Flag-tagged intracellular region of EDAR (EDARIC) together with a plasmid expressing N-terminal c-myc-tagged EDARADD. Flag-tagged EDARIC was precipitated with mouse anti-Flag affinity gels (Sigma) and the binding of c-myc-tagged EDARADD was detected by rabbit anti-c-myc western blotting (top panel). The expression levels of Flag-tagged EDARIC (middle panel) and c-myc-tagged EDARADD (bottom panel) are also shown. Note that wild-type (WT) EDARIC successfully co-precipitated with EDARADD, whereas R375H mutant EDAR completely lost this interaction. Journal of Investigative Dermatology 2004 123, 649-655DOI: (10.1111/j.0022-202X.2004.23405.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 The activation of NF-κB by wild-type or mutant EDAR. HEK293T cells were transfected with 0.1 μg of pNF-κBLuc luciferase reporter vector (Clontech), 25 ng of pRL-TK vector (Promega), with or without 0.1 μg of each expression construct. The reporter gene activity was determined with the Dual-Luciferase Reporter Assay System (Promega). The expression levels of Flag-tagged EDAR are shown at the bottom. Note that R375H mutant EDAR markedly reduced the activation of NF-κB compared to wild-type EDAR. Journal of Investigative Dermatology 2004 123, 649-655DOI: (10.1111/j.0022-202X.2004.23405.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Clinical appearance of the patient with HED. (a) Her facial features were notable for a saddle nose, periorbital wrinkling, and hyperpigmentation. The hair of the scalp, eyebrows and eyelashes were sparse. (b) She had oligodontia with only two permanent, conical teeth. Journal of Investigative Dermatology 2004 123, 649-655DOI: (10.1111/j.0022-202X.2004.23405.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions