Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy.
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.
Schröder
Rolf
R
Department of Neurology, University of Bonn, Germany.
Kunz
Wolfram S
WS
Rouan
Fatima
F
Pfendner
Ellen
E
Tolksdorf
Karen
K
Kappes-Horn
Karin
K
Altenschmidt-Mehring
Manuela
M
Knoblich
Rupert
R
van der Ven
Peter F M
PF
Reimann
Jens
J
Fürst
Dieter O
DO
Blümcke
Ingmar
I
Vielhaber
Stefan
S
Zillikens
Detlef
D
Eming
Sabine
S
Klockgether
Thomas
T
Uitto
Jouni
J
Wiche
Gerhard
G
Rolfs
Arndt
A
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
D003893:Desmin; D007381:Intermediate Filament Proteins; C495332:PLEC protein, human; D051190:Plectin