title: De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy.
abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease, frequently accompanied by sudden cardiac death and terminal heart failure. Genotyping of ARVC patients might be used for palliative treatment of the affected family. We genotyped a cohort of 22 ARVC patients referred to molecular genetic screening in our heart center for mutations in the desmosomal candidate genes JUP, DSG2, DSC2, DSP and PKP2 known to be associated with ARVC. In 43% of the cohort, we found disease-associated sequence variants. In addition, we screened for desmin mutations and found a novel desmin-mutation p.N116S in a patient with ARVC and terminal heart failure, which is located in segment 1A of the desmin rod domain. The mutation leads to the aggresome formation in cardiac and skeletal muscle without signs of an overt clinical myopathy. Cardiac aggresomes appear to be prominent, especially in the right ventricle of the heart. Viscosimetry and atomic force microscopy of the desmin wild-type and N116S mutant isolated from recombinant Escherichia coli revealed severe impairment of the filament formation, which was supported by transfections in SW13 cells. Thus, the gene coding for desmin appears to be a novel ARVC gene, which should be included in molecular genetic screening of ARVC patients.
authors.affiliation: Herz- & Diabeteszentrum NRW, Klinik f. Thorax- und Kardiovaskularchirurgie, Erich und Hanna Klessmann-Institutfür Kardiovaskulaere Forschung und Entwicklung/Klinik fuer angeborene Herzfehler, Georgstrasse 11, Bad Oeynhausen, Germany.
authors.forename: Baerbel
authors.initials: B
authors.lastname: Klauke
authors.forename: Sabine
authors.initials: S
authors.lastname: Kossmann
authors.forename: Anna
authors.initials: A
authors.lastname: Gaertner
authors.forename: Kristina
authors.initials: K
authors.lastname: Brand
authors.forename: Ines
authors.initials: I
authors.lastname: Stork
authors.forename: Andreas
authors.initials: A
authors.lastname: Brodehl
authors.forename: Mareike
authors.initials: M
authors.lastname: Dieding
authors.forename: Volker
authors.initials: V
authors.lastname: Walhorn
authors.forename: Dario
authors.initials: D
authors.lastname: Anselmetti
authors.forename: Désirée
authors.initials: D
authors.lastname: Gerdes
authors.forename: Birte
authors.initials: B
authors.lastname: Bohms
authors.forename: Uwe
authors.initials: U
authors.lastname: Schulz
authors.forename: Edzard
authors.initials: E
authors.lastname: Zu Knyphausen
authors.forename: Matthias
authors.initials: M
authors.lastname: Vorgerd
authors.forename: Jan
authors.initials: J
authors.lastname: Gummert
authors.forename: Hendrik
authors.initials: H
authors.lastname: Milting
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000473:pathology*; D001483:Base Sequence; D002448:Cell Adhesion / Q000235:genetics; D016757:Death, Sudden, Cardiac / Q000209:etiology; D003893:Desmin / Q000235:genetics*; D003896:Desmosomes / Q000235:genetics* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007382:Intermediate Filaments / Q000235:genetics; D008297:Male; D018625:Microscopy, Atomic Force; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction
chemical_list: D003893:Desmin