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.

Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation

“…9 Right ventricular cardiomyopathy and ARVC that were present in individuals of this family have been linked to DES mutations in recent years. [10][11][12][13] In conclusion, we have, by means of exome sequencing, identified the causative DES mutation in a family with MFM and ARVC. Our results demonstrate diagnostic difficulties with some forms of dominantly inherited muscle diseases as they can display a wide clinical and morphological variability even within a given family.…”

Desmoglein 2–Dependent Arrhythmogenic Cardiomyopathy Is Caused by a Loss of Adhesive Function

“…46 A provocative conclusion is that downregulation of Pg and Pkp2 may also lead to weakening of desmosomal cadherin-mediated adhesion and desmin intermediate filament anchorage. DSP mutations 31,45 and certain desmin mutations 47,48 may contribute in a similar fashion to impair the stability and resilience of the desmosome-based transcellular scaffold. Thus, altered adhesion may be the primary dysfunction of desmosome-related cardiomyopathy that can be brought about in different ways as reflected by the different desmosomal gene mutations reported to date.…”

Compound and Digenic Heterozygosity in Desmosome Genes as a Cause of Arrhythmogenic Right Ventricular Cardiomyopathy in Japanese Patients

“…A genetic analysis of patients with ARVC identified at least 8 different causative genes, mostly desmosome genes, including junction plakoglobin (JUP), 1 desmoplakin (DSP), 2,3 plakophilin-2 (PKP2), 4-6 desmoglein-2 (DSG2), 7 desmocollin-2 (DSC2), 8 and desmin (DES), 9 thus revealing the genetic heterogeneity of the disease.…”