title: Alterations in desmosome size and number coincide with the loss of keratinocyte cohesion in skin with homozygous and heterozygous defects in the desmosomal protein plakophilin 1.
abstract: Recessive mutations in the desmosomal plaque protein plakophilin 1 (PkP1) underlie ectodermal dysplasia/skin fragility syndrome (MIM 604536). We undertook an immunohistochemical and quantitative electron microscopic examination of suprabasal desmosomes from 4 skin samples from 3 PkP1 deficient patients, an unaffected carrier with a PKP1 heterozygous acceptor splice site mutation and 5 healthy control subjects. Desmosomal plaque size (>50 desmosomes per individual) and frequency (>20 high power fields, HPF) were assessed. Compared with controls, desmosomes were reduced dramatically both in size (49%) and frequency (61%) in the lower suprabasal layers (LSB) in PkP1 null patients (P<0.01). In the LSB compartment of the heterozygous carrier, corresponding reductions were 37% and 20%, respectively (P<0.01). Surprisingly, the PkP1 null patient's upper suprabasal layer, (USB), desmosome size was larger (59%, P<0.01) than the control value, and showed increased desmoglein 1 and PkP2 USB staining. The USB desmosome frequency in PKP1 null patients was similar to the LSB compartment (but reduced by 43% compared to USB controls). The carrier showed no difference in the USB desmosome size and frequency compared with the controls (P>0.05). The PKP1 null patients showed poorly developed inner and outer desmosomal plaques. Thus, both the patients and unaffected carrier showed reductions in the LSB desmosome size and number; despite only PkP1 null patients exhibiting any phenotype. These findings attest to the molecular recruiting and stabilizing roles of PkP1 in desmosome formation, particularly in the LSB compartment.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. jrm57@med.hokudai.ac.jp
authors.forename: James R
authors.initials: JR
authors.lastname: McMillan
authors.forename: Marek
authors.initials: M
authors.lastname: Haftek
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.forename: Andrew P
authors.initials: AP
authors.lastname: South
authors.forename: Henri
authors.initials: H
authors.lastname: Perrot
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Eady
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal; D002675:Child, Preschool; D003896:Desmosomes / Q000473:pathology* / Q000648:ultrastructure; D004817:Epidermis / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015603:Keratinocytes / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D051191:Plakophilins; D011506:Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D012871:Skin Diseases / Q000235:genetics / Q000473:pathology*
chemical_list: D000911:Antibodies, Monoclonal; C495335:PKP1 protein, human; C495337:PKP2 protein, human; D051191:Plakophilins; D011506:Proteins