title: Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network.
abstract: BACKGROUND
  Several hereditary human diseases are now known to be caused by distinct mutations in genes encoding various desmosome components. Although the effects of some of these mutant genes have been analysed by targeted disruption experiments in mouse models, little is known about the cell and tissue changes in affected human patients.
  
  
  OBJECTIVE
  To investigate the effects of heterozygous nonsense mutations in desmoplakin (Dp) and desmoglein (Dsg) 1 which cause the autosomal dominant disorder striate palmoplantar keratoderma (SPPK), focusing on changes in desmosome structure and composition and the associated keratin intermediate filament (KIF) network in palm skin, and in cultured keratinocytes generated from the same site.
  
  
  METHODS
  We analysed palm and nonpalm skin sections from four SPPK patients with Dp mutations and one patient with a Dsg1 mutation with respect to tissue and subcellular morphologies, and correlated the in vivo and in vitro findings.
  
  
  RESULTS
  Using electron microscopy, we found abnormalities of desmosomes and cell-cell adhesion in the suprabasal layers in the epidermis from patients with both Dsg1- and Dp-associated SPPK. These changes were more advanced in skin from patients with Dp mutations. Both Dp and Dsg1 mutations were accompanied by significantly reduced numbers of desmosomes in the suprabasal layers, while decreased desmosome size was evident only in Dsg1-associated SPPK. Confocal microscopy analysis showed marked differences in the expression of keratins and of desmosome components, both between the two types of SPPK, and between SPPK and normal skin. The expression of keratins K5, K14 and K10 was reduced in Dsg1-associated SPPK skin, whereas perinuclear aggregation of keratin filaments was more evident in Dp-associated SPPK. In both types of SPPK upregulation of K16 was pronounced and involucrin labelling was abnormal.
  
  
  CONCLUSIONS
  Mutations in Dp and Dsg1 genes causing SPPK may be associated with perturbations in epidermal differentiation accompanied by a marked disruption of several components of the epidermal scaffold including desmosomes and the KIF network.
authors.affiliation: Genetic Skin Disease Group, Divison of Skin Scinces, The Rayne Institute, Guy's, King's and St Thomas' School of Medicine, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.
authors.forename: H
authors.initials: H
authors.lastname: Wan
authors.forename: P J C
authors.initials: PJ
authors.lastname: Dopping-Hepenstal
authors.forename: M J
authors.initials: MJ
authors.lastname: Gratian
authors.forename: M G
authors.initials: MG
authors.lastname: Stone
authors.forename: G
authors.initials: G
authors.lastname: Zhu
authors.forename: P E
authors.initials: PE
authors.lastname: Purkis
authors.forename: A P
authors.initials: AP
authors.lastname: South
authors.forename: F
authors.initials: F
authors.lastname: Keane
authors.forename: D K B
authors.initials: DK
authors.lastname: Armstrong
authors.forename: R S
authors.initials: RS
authors.lastname: Buxton
authors.forename: J A
authors.initials: JA
authors.lastname: McGrath
authors.forename: R A J
authors.initials: RA
authors.lastname: Eady
mesh_terms: D000328:Adult; D000368:Aged; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D051183:Desmoglein 1; D051182:Desmogleins; D051180:Desmoplakins; D003896:Desmosomes / Q000235:genetics / Q000648:ultrastructure*; D004817:Epidermis / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007633:Keratins / Q000378:metabolism; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008854:Microscopy, Electron; D008875:Middle Aged; D011498:Protein Precursors / Q000378:metabolism
chemical_list: D015820:Cadherins; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; C495297:DSG1 protein, human; C495294:DSP protein, human; D051183:Desmoglein 1; D051182:Desmogleins; D051180:Desmoplakins; D011498:Protein Precursors; C032253:involucrin; D007633:Keratins