De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy

• Published in: Human molecular genetics 2010-12, Vol.19 (23), p.4595-4607
• Main Authors: Klauke, Baerbel, Kossmann, Sabine, Gaertner, Anna, Brand, Kristina, Stork, Ines, Brodehl, Andreas, Dieding, Mareike, Walhorn, Volker, Anselmetti, Dario, Gerdes, Désirée, Bohms, Birte, Schulz, Uwe, zu Knyphausen, Edzard, Vorgerd, Matthias, Gummert, Jan, Milting, Hendrik
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Arrhythmogenic Right Ventricular Dysplasia - genetics; Arrhythmogenic Right Ventricular Dysplasia - pathology; Base Sequence; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Cell Adhesion - genetics; Death, Sudden, Cardiac - etiology; Desmin - genetics; Desmosomes - genetics; Desmosomes - pathology; Escherichia coli; Female; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Genetic Predisposition to Disease; Genetic Testing; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Heart; Humans; Intermediate Filaments - genetics; Male; Medical sciences; Microscopy, Atomic Force; Middle Aged; Molecular and cellular biology; Mutation; Polymerase Chain Reaction
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddq387

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.