De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy.
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.
Klauke
Baerbel
B
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.
Kossmann
Sabine
S
Gaertner
Anna
A
Brand
Kristina
K
Stork
Ines
I
Brodehl
Andreas
A
Dieding
Mareike
M
Walhorn
Volker
V
Anselmetti
Dario
D
Gerdes
Désirée
D
Bohms
Birte
B
Schulz
Uwe
U
Zu Knyphausen
Edzard
E
Vorgerd
Matthias
M
Gummert
Jan
J
Milting
Hendrik
H
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
D003893:Desmin