title: The novel desmin mutant p.A120D impairs filament formation, prevents intercalated disk localization, and causes sudden cardiac death.
abstract: BACKGROUND
  The intermediate filament protein desmin is encoded by the gene DES and contributes to the mechanical stabilization of the striated muscle sarcomere and cell contacts within the cardiac intercalated disk. DES mutations cause severe skeletal and cardiac muscle diseases with heterogeneous phenotypes. Recently, DES mutations were also found in patients with arrhythmogenic right ventricular cardiomyopathy. Currently, the cellular and molecular pathomechanisms of the DES mutations leading to this disease are not exactly known.
  
  
  RESULTS
  We identified the 2 novel variants DES-p.A120D (c.359C>A) and DES-p.H326R (c.977A>G), which were characterized by cell culture experiments and atomic force microscopy. Family analysis indicated a broad spectrum of cardiomyopathies with a striking frequency of arrhythmias and sudden cardiac deaths. The in vitro experiments of desmin-p.A120D reveal a severe intrinsic filament formation defect causing cytoplasmic aggregates in cell lines and of the isolated recombinant protein. Model variants of codon 120 indicated that ionic interactions contribute to this filament formation defect. Ex vivo analysis of ventricular tissue slices revealed a loss of desmin staining within the intercalated disk and severe cytoplasmic aggregate formation, whereas z-band localization was not affected. The functional experiments of desmin-p.H326R did not demonstrate any differences from wild type.
  
  
  CONCLUSIONS
  Because of the functional in vivo and in vitro characterization, DES-p.A120D has to be regarded as a pathogenic mutation and DES-p.H326R as a rare variant with unknown significance. Presumably, the loss of the desmin-p. A120D filament localization at the intercalated disk explains its clinical arrhythmogenic potential.
authors.forename: Andreas
authors.initials: A
authors.lastname: Brodehl
authors.forename: Mareike
authors.initials: M
authors.lastname: Dieding
authors.forename: Bärbel
authors.initials: B
authors.lastname: Klauke
authors.forename: Eric
authors.initials: E
authors.lastname: Dec
authors.forename: Shrestha
authors.initials: S
authors.lastname: Madaan
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.forename: John
authors.initials: J
authors.lastname: Gargus
authors.forename: Azra
authors.initials: A
authors.lastname: Fatima
authors.forename: Tomo
authors.initials: T
authors.lastname: Saric
authors.forename: Hamdin
authors.initials: H
authors.lastname: Cakar
authors.forename: Volker
authors.initials: V
authors.lastname: Walhorn
authors.forename: Katja
authors.initials: K
authors.lastname: Tönsing
authors.forename: Tim
authors.initials: T
authors.lastname: Skrzipczyk
authors.forename: Ramona
authors.initials: R
authors.lastname: Cebulla
authors.forename: Désirée
authors.initials: D
authors.lastname: Gerdes
authors.forename: Uwe
authors.initials: U
authors.lastname: Schulz
authors.forename: Jan
authors.initials: J
authors.lastname: Gummert
authors.forename: Jesper Hastrup
authors.initials: JH
authors.lastname: Svendsen
authors.forename: Morten Salling
authors.initials: MS
authors.lastname: Olesen
authors.forename: Dario
authors.initials: D
authors.lastname: Anselmetti
authors.forename: Alex Hørby
authors.initials: AH
authors.lastname: Christensen
authors.forename: Virginia
authors.initials: V
authors.lastname: Kimonis
authors.forename: Hendrik
authors.initials: H
authors.lastname: Milting
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac; D003893:Desmin / Q000235:genetics* / Q000378:metabolism; D003896:Desmosomes / Q000378:metabolism; D005192:Family Health; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007382:Intermediate Filaments / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018625:Microscopy, Atomic Force; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: D003893:Desmin
keywords: arrhythmias, cardiac; cardiomyopathies; death, sudden; desmin; desmosomes; intermediate filaments