The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death

• DOI: 10.1161/circgenetics.113.000103
• Publication Date: 2013-11-08T04:58:18Z
• Authors: Andreas Brodehl; Mareike Dieding; Bärbel Klauke; Eric Dec; Shrestha Madaan; Taosheng Huang; John Gargus; Azra Fatima; Tomo Šaric; Hamdin Cakar; Volker Walhorn; Katja Tönsing; Tim Skrzipczyk; Ramona Cebulla; Désirée Gerdes; Uwe Schulz; Jan Gummert; Jesper Hastrup Sv...; Morten Salling Ol...; Dario Anselmetti; Alex Hørby Christ...; Virginia Kimonis; Hendrik Milting
• Keywords: Desmin; Sudden Death

The intermediate filament protein desmin is encoded by the gene DES and contributes to mechanical stabilization of striated muscle sarcomere cell contacts within cardiac intercalated disk. mutations cause severe skeletal diseases with heterogeneous phenotypes. Recently, were also found in patients arrhythmogenic right ventricular cardiomyopathy. Currently, cellular molecular pathomechanisms leading this disease are not exactly known.We identified 2 novel variants DES-p.A120D (c.359C>A) DES-p.H326R (c.977A>G), which characterized culture experiments atomic force microscopy. Family analysis indicated a broad spectrum cardiomyopathies striking frequency arrhythmias sudden deaths. vitro desmin-p.A120D reveal intrinsic formation defect causing cytoplasmic aggregates lines isolated recombinant protein. Model codon 120 that ionic interactions contribute defect. Ex vivo tissue slices revealed loss staining disk aggregate formation, whereas z-band localization was affected. functional desmin-p.H326R did demonstrate any differences from wild type.Because characterization, has be regarded as pathogenic mutation rare variant unknown significance. Presumably, desmin-p. A120D at explains its clinical potential.