title: Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy.
abstract: Mutations of the human plectin gene (Plec1) cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). Here, we report on molecular mechanisms leading to severe dystrophic muscle alterations in EBS-MD. Analysis of a 25-yr-old EBS-MD patient carrying a novel homozygous 16-bp insertion mutation (13803ins16/13803ins16) close to the intermediate filament (IF) binding site of plectin showed severe disorganization of the myogenic IF cytoskeleton. Intermyofibrillar and subsarcolemmal accumulations of assembled but highly unordered desmin filaments may be attributed to impaired desmin binding capability of the mutant plectin. This IF pathology was also associated with severe mitochondrial dysfunction, suggesting that the muscle pathology of EBS-MD caused by IF disorganization leads not only to defects in mechanical force transduction but also to metabolic dysfunction. Beyond EBS-MD, our data may contribute to the understanding of other myopathies characterized by sarcoplasmic IF accumulations such as desminopathies or alpha-B-crystallinopathies.
authors.affiliation: Department of Neurology, University of Bonn, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Schröder
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.forename: Fatima
authors.initials: F
authors.lastname: Rouan
authors.forename: Ellen
authors.initials: E
authors.lastname: Pfendner
authors.forename: Karen
authors.initials: K
authors.lastname: Tolksdorf
authors.forename: Karin
authors.initials: K
authors.lastname: Kappes-Horn
authors.forename: Manuela
authors.initials: M
authors.lastname: Altenschmidt-Mehring
authors.forename: Rupert
authors.initials: R
authors.lastname: Knoblich
authors.forename: Peter F M
authors.initials: PF
authors.lastname: van der Ven
authors.forename: Jens
authors.initials: J
authors.lastname: Reimann
authors.forename: Dieter O
authors.initials: DO
authors.lastname: Fürst
authors.forename: Ingmar
authors.initials: I
authors.lastname: Blümcke
authors.forename: Stefan
authors.initials: S
authors.lastname: Vielhaber
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Sabine
authors.initials: S
authors.lastname: Eming
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wiche
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D003893:Desmin / Q000032:analysis*; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics / Q000473:pathology*; D005123:Eye / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D007382:Intermediate Filaments / Q000737:chemistry / Q000473:pathology*; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000473:pathology* / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D051190:Plectin; D012867:Skin / Q000473:pathology
chemical_list: D003893:Desmin; D007381:Intermediate Filament Proteins; C495332:PLEC protein, human; D051190:Plectin