title: Skin fragility and hypohidrotic ectodermal dysplasia resulting from ablation of plakophilin 1.
abstract: We report a 2-year-old boy with an unusual autosomal recessively inherited skin disease comprising trauma-induced skin fragility and congenital ectodermal dysplasia affecting hair, nails and sweat glands. Skin biopsy showed widening of intercellular spaces between keratinocytes and ultrastructural findings of small, poorly formed desmosomes with reduced connections to the keratin filament cytoskeleton. Immunohistochemical analysis revealed a complete absence of staining for the accessory desmosomal plaque protein plakophilin 1 (PKP1; band 6 protein). The affected individual was a compound heterozygote for null mutations on both alleles of the PKP1 gene. Both mutations occurred within the amino terminus of PKP1, the domain which normally binds the cytoskeletal keratin filament network to the cell membrane. Apart from its localization within desmosomal plaques, PKP1 may also be present within the cytoplasm and nucleus and has putative roles in signal transduction and regulation of gene activity. The clinicopathological observations in this patient demonstrate the relevance of PKP1 to desmosome formation, cutaneous cell-cell adhesion and epidermal development and demonstrate the specific manifestations of human functional knockout mutations in this gene.
authors.affiliation: Department of Cell and Molecular Pathology, St John's Institute of Dermatology (Guy's, Kings College and St Thomas' Hospitals' Medical School), St Thomas' Hospital, London SE1 7EH, U.K. j.mcgrath@umds.ac.uk
authors.forename: J A
authors.initials: JA
authors.lastname: McGrath
authors.forename: P H
authors.initials: PH
authors.lastname: Hoeger
authors.forename: A M
authors.initials: AM
authors.lastname: Christiano
authors.forename: J R
authors.initials: JR
authors.lastname: McMillan
authors.forename: J E
authors.initials: JE
authors.lastname: Mellerio
authors.forename: G H
authors.initials: GH
authors.lastname: Ashton
authors.forename: P J
authors.initials: PJ
authors.lastname: Dopping-Hepenstal
authors.forename: B D
authors.initials: BD
authors.lastname: Lake
authors.forename: I M
authors.initials: IM
authors.lastname: Leigh
authors.forename: J I
authors.initials: JI
authors.lastname: Harper
authors.forename: R A
authors.initials: RA
authors.lastname: Eady
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000235:genetics; D006801:Humans; D007007:Hypohidrosis / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D051191:Plakophilins; D011506:Proteins / Q000235:genetics*; D012871:Skin Diseases / Q000235:genetics* / Q000473:pathology
chemical_list: C495335:PKP1 protein, human; D051191:Plakophilins; D011506:Proteins