Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex.
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.
Natsuga
Ken
K
Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Nishie
Wataru
W
Akiyama
Masashi
M
Nakamura
Hideki
H
Shinkuma
Satoru
S
McMillan
James R
JR
Nagasaki
Akari
A
Has
Cristina
C
Ouchi
Takeshi
T
Ishiko
Akira
A
Hirako
Yoshiaki
Y
Owaribe
Katsushi
K
Sawamura
Daisuke
D
Bruckner-Tuderman
Leena
L
Shimizu
Hiroshi
H
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
D051190:Plectin; D020033:Protein Isoforms; D012333:RNA, Messenger