Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy.
Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients. PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.(Phe755del) and p.(Lys1040Argfs*139)) mutations resulting in complete abolition of plectin protein expression. In contrast, the other two patients with different homozygous PLEC mutations showed preserved plectin protein expression with one only expressing rodless plectin variants, and the other markedly reduced protein levels. Analysis of skeletal muscle tissue from all three patients revealed severe disruption of the extrasarcomeric intermediate filament cytoskeleton, protein aggregates positive for desmin, syncoilin, and synemin, degenerative myofibrillar changes, and mitochondrial abnormalities comprising respiratory chain dysfunction and an altered organelle distribution and amount.Our study demonstrates that EBS-MD causing PLEC mutations universally result in a desmin protein aggregate myopathy phenotype despite marked differences in individual plectin protein expression patterns. Since plectin is the key cytolinker protein that regulates the structural and functional organization of desmin filaments, the defective anchorage and spacing of assembled desmin filaments is the key pathogenetic event that triggers the formation of desmin protein aggregates as well as secondary mitochondrial pathology.
Institute of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany.
Lilli
L
Winter
Department of Neurology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Matthias
M
Türk
Institute of Neurology (Edinger Institute), Goethe University Frankfurt, Frankfurt, Germany.
Patrick N
PN
Harter
Institute of Neurology (Edinger Institute), Goethe University Frankfurt, Frankfurt, Germany.
Michel
M
Mittelbronn
Department of Neurology, University Hospital of Bonn, Bonn, Germany.|Center for Rare Diseases Bonn (ZSEB), University Hospital of Bonn, Bonn, Germany.
Cornelia
C
Kornblum
Department of Neurology, Ruskin Wing, King's College Hospital, London, UK.
Fiona
F
Norwood
Department of Paediatric Neurology, Neuromuscular Service, Evelina Children's Hospital, St Thomas' Hospital, London, UK.|Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, UK.|Department of Basic and Clinical Neuroscience, IoPPN, King's College, London, UK.
Heinz
H
Jungbluth
Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Christian T
CT
Thiel
Department of Opthalmology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Ursula
U
Schlötzer-Schrehardt
Institute of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany. rolf.schroeder@uk-erlangen.de.
Rolf
R
Schröder
D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D051190:Plectin / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
C495332:PLEC protein, human; D051190:Plectin
Desmin; Epidermolysis bullosa simplex with muscular dystrophy; Intermediate filaments; Mitochondria; Plectin; Protein aggregates; Skeletal muscle