title: Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies.
abstract: Myofibrillar myopathy (MFM) encompasses a genetically heterogeneous group of human diseases caused by mutations in genes coding for structural proteins of muscle. Mutations in the intermediate filament (IF) protein desmin (DES), a major cytoskeletal component of myocytes, lead to severe forms of "desminopathy," which affects cardiac, skeletal, and smooth muscle. Most mutations described reside in the central alpha-helical rod domain of desmin. Here we report three novel mutations--c.1325C>T (p.T442I), c.1360C>T (p.R454W), and c.1379G>T (p.S460I)--located in desmin's non-alpha-helical carboxy-terminal "tail" domain. We have investigated the impact of these and four--c.1237G>A (p.E413K), c.1346A>C (p.K449T), c.1353C>G (p.I451M), and c.1405G>A (p.V469M)--previously described "tail" mutations on in vitro filament formation and on the generation of ordered cytoskeletal arrays in transfected myoblasts. Although all but two mutants (p.E413K, p.R454W) assembled into IFs in vitro and all except p.E413K were incorporated into IF arrays in transfected C2C12 cells, filament properties differed significantly from wild-type desmin as revealed by viscometric assembly assays. Most notably, when coassembled with wild-type desmin, these mutants revealed a severe disturbance of filament-formation competence and filament-filament interactions, indicating an inherent incompatibility of mutant and wild-type protein to form mixed filaments. The various clinical phenotypes observed may reflect altered interactions of desmin's tail domain with different components of the myoblast cytoskeleton leading to diminished biomechanical properties and/or altered metabolism of the individual myocyte. Our in vitro assembly regimen proved to be a very sensible tool to detect if a particular desmin mutation is able to cause filament abnormalities.
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Bär
authors.forename: Bertrand
authors.initials: B
authors.lastname: Goudeau
authors.forename: Sarah
authors.initials: S
authors.lastname: Wälde
authors.forename: Monique
authors.initials: M
authors.lastname: Casteras-Simon
authors.forename: Norbert
authors.initials: N
authors.lastname: Mücke
authors.forename: Alexey
authors.initials: A
authors.lastname: Shatunov
authors.forename: Y Paul
authors.initials: YP
authors.lastname: Goldberg
authors.forename: Charles
authors.initials: C
authors.lastname: Clarke
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Michel
authors.initials: M
authors.lastname: Fardeau
authors.forename: Lev
authors.initials: L
authors.lastname: Goldfarb
authors.forename: Patrick
authors.initials: P
authors.lastname: Vicart
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D003893:Desmin / Q000235:genetics* / Q000378:metabolism; D016189:Dystrophin / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D017354:Point Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D038203:alpha-Crystallin B Chain / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D003893:Desmin; D016189:Dystrophin; D038203:alpha-Crystallin B Chain