title: Plectin defects in epidermolysis bullosa simplex with muscular dystrophy.
abstract: Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD, MIM 226670) is caused by plectin defects. We performed mutational analysis and immunohistochemistry using EBS-MD (n = 3 cases) and control skeletal muscle to determine pathogenesis. Mutational analysis revealed a novel homozygous plectin-exon32 rod domain mutation (R2465X). All plectin/HD1-121 antibodies stained the control skeletal muscle membrane. However, plectin antibodies stained the cytoplasm of type II control muscle fibers (as confirmed by ATPase staining), whereas HD1-121 stained the cytoplasm of type I fibers. EBS-MD samples lacked membrane (n = 3) but retained cytoplasmic HD1-121 (n = 1) and plectin staining in type II fibers (n = 3). Ultrastructurally, EBS-MD demonstrated widening and vacuolization adjacent to the membrane and disorganization of Z-lines (n = 2 of 3) compared to controls (n = 5). Control muscle immunogold labeling colocalized plectin and desmin to filamentous bridges between Z-lines and the membrane that were disrupted in EBS-MD muscle. We conclude that fiber-specific plectin expression is associated with the desmin-cytoskeleton, Z-lines, and crucially myocyte membrane linkage, analogous to hemidesmosomes in skin.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan. jrm57@med.hokudai.ac.jp
authors.forename: J R
authors.initials: JR
authors.lastname: McMillan
authors.forename: M
authors.initials: M
authors.lastname: Akiyama
authors.forename: F
authors.initials: F
authors.lastname: Rouan
authors.forename: J E
authors.initials: JE
authors.lastname: Mellerio
authors.forename: E B
authors.initials: EB
authors.lastname: Lane
authors.forename: I M
authors.initials: IM
authors.lastname: Leigh
authors.forename: K
authors.initials: K
authors.lastname: Owaribe
authors.forename: G
authors.initials: G
authors.lastname: Wiche
authors.forename: N
authors.initials: N
authors.lastname: Fujii
authors.forename: J
authors.initials: J
authors.lastname: Uitto
authors.forename: R A J
authors.initials: RA
authors.lastname: Eady
authors.forename: H
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000328:Adult; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002648:Child; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004252:DNA Mutational Analysis; D003896:Desmosomes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016110:Epidermolysis Bullosa Simplex / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009136:Muscular Dystrophies / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D051190:Plectin / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D051190:Plectin