title: Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex.
abstract: Plectin is a cytoskeletal linker protein that has a dumbbell-like structure with a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC1) cause two distinct autosomal recessive subtypes of epidermolysis bullosa (EB): EB simplex with muscular dystrophy (EBS-MD), and EB simplex with pyloric atresia (EBS-PA). Here, we demonstrate that normal human fibroblasts express two different plectin isoforms including full-length and rodless forms of plectin. We performed detailed analysis of plectin expression patterns in six EBS-MD and three EBS-PA patients. In EBS-PA, expression of all plectin domains was found to be markedly attenuated or completely lost; in EBS-MD, the expression of the N- and C-terminal domains of plectin remained detectable, although the expression of rod domains was absent or markedly reduced. Our data suggest that loss of the full-length plectin isoform with residual expression of the rodless plectin isoform leads to EBS-MD, and that complete loss or marked attenuation of full-length and rodless plectin expression underlies the more severe EBS-PA phenotype. These results also clearly account for the majority of EBS-MD PLEC1 mutation restriction within the large exon 31 that encodes the plectin rod domain, whereas EBS-PA PLEC1 mutations are generally outside exon 31.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Natsuga
authors.forename: Wataru
authors.initials: W
authors.lastname: Nishie
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinkuma
authors.forename: James R
authors.initials: JR
authors.lastname: McMillan
authors.forename: Akari
authors.initials: A
authors.lastname: Nagasaki
authors.forename: Cristina
authors.initials: C
authors.lastname: Has
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ouchi
authors.forename: Akira
authors.initials: A
authors.lastname: Ishiko
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Hirako
authors.forename: Katsushi
authors.initials: K
authors.lastname: Owaribe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sawamura
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000465:Algorithms; D004252:DNA Mutational Analysis; D016110:Epidermolysis Bullosa Simplex / Q000175:diagnosis / Q000378:metabolism*; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D008856:Microscopy, Fluorescence / Q000379:methods; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D051190:Plectin / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D051190:Plectin; D020033:Protein Isoforms; D012333:RNA, Messenger