title: A rare case of hypohidrotic ectodermal dysplasia caused by compound heterozygous mutations in the EDAR gene.
abstract: Hypohidrotic ectodermal dysplasia (HED) is a genetic disease characterized by abnormal hair, teeth, and sweat gland development. Although most cases of HED display X-linked recessive inheritance, autosomal dominant and autosomal recessive forms also exist. X-linked HED is caused by mutations in the EDA gene, and the autosomal forms result from mutations in either the EDAR gene or the EDARADD gene. In this study, we identified compound heterozygous mutations in the EDAR gene in a Japanese female patient with HED. On the maternal allele is a novel splice donor site mutation of intron 2 leading to the generation of unstable transcripts with exon 2 skipping; on the paternal allele is a novel R375H transition within the death domain of EDAR. Using expression studies in tissue culture cells, we found that the R375H substitution in EDAR caused loss of its affinity for EDARADD and reduced activation of the downstream target NF-kappaB. Our findings indicate that both alleles of EDAR are non-functional in our patient, resulting in the HED phenotype.
authors.affiliation: Department of Dermatology, Niigata University School of Medicine, Niigata, Japan. yshimo@med.niigata-u.ac.jp
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimomura
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sato
authors.forename: Akinori
authors.initials: A
authors.lastname: Miyashita
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
mesh_terms: D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D004476:Ectodermal Dysplasia / Q000235:genetics*; D053339:Edar Receptor; D005091:Exons; D005260:Female; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007007:Hypohidrosis / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor
chemical_list: C506008:EDAR protein, human; D053339:Edar Receptor; D008565:Membrane Proteins; D016328:NF-kappa B; D022821:RNA Splice Sites; D012333:RNA, Messenger; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor