Universität zu Köln

Brodehl, Andreas ORCID: 0000-0001-9202-2343, Dieding, Mareike, Klauke, Baerbel, Dec, Eric, Madaan, Shrestha, Huang, Taosheng ORCID: 0000-0001-6601-6687, Gargus, John, Fatima, Azra, Saric, Tomo ORCID: 0000-0001-8344-1095, Cakar, Hamdin, Walhorn, Volker, Toensing, Katja, Skrzipczyk, Tim, Cebulla, Ramona, Gerdes, Desiree, Schulz, Uwe, Gummert, Jan, Svendsen, Jesper Hastrup ORCID: 0000-0001-8466-8515, Olesen, Morten Salling ORCID: 0000-0001-9477-5322, Anselmetti, Dario ORCID: 0000-0002-8720-4369, Christensen, Alex Horby, Kimonis, Virginia and Milting, Hendrik (2013). The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac. Circ.-Cardiovasc. Genet., 6 (6). S. 615 - 624. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1942-3268

Full text not available from this repository.

Abstract

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

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Brodehl, Andreas UNSPECIFIED orcid.org/0000-0001-9202-2343 UNSPECIFIED Dieding, Mareike UNSPECIFIED UNSPECIFIED UNSPECIFIED Klauke, Baerbel UNSPECIFIED UNSPECIFIED UNSPECIFIED Dec, Eric UNSPECIFIED UNSPECIFIED UNSPECIFIED Madaan, Shrestha UNSPECIFIED UNSPECIFIED UNSPECIFIED Huang, Taosheng UNSPECIFIED orcid.org/0000-0001-6601-6687 UNSPECIFIED Gargus, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Fatima, Azra UNSPECIFIED UNSPECIFIED UNSPECIFIED Saric, Tomo UNSPECIFIED orcid.org/0000-0001-8344-1095 UNSPECIFIED Cakar, Hamdin UNSPECIFIED UNSPECIFIED UNSPECIFIED Walhorn, Volker UNSPECIFIED UNSPECIFIED UNSPECIFIED Toensing, Katja UNSPECIFIED UNSPECIFIED UNSPECIFIED Skrzipczyk, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED Cebulla, Ramona UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerdes, Desiree UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulz, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Gummert, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Svendsen, Jesper Hastrup UNSPECIFIED orcid.org/0000-0001-8466-8515 UNSPECIFIED Olesen, Morten Salling UNSPECIFIED orcid.org/0000-0001-9477-5322 UNSPECIFIED Anselmetti, Dario UNSPECIFIED orcid.org/0000-0002-8720-4369 UNSPECIFIED Christensen, Alex Horby UNSPECIFIED UNSPECIFIED UNSPECIFIED Kimonis, Virginia UNSPECIFIED UNSPECIFIED UNSPECIFIED Milting, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-471361
DOI:	10.1161/CIRCGENETICS.113.000103
Journal or Publication Title:	Circ.-Cardiovasc. Genet.
Volume:	6
Number:	6
Page Range:	S. 615 - 624
Date:	2013
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1942-3268
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EPIDERMOLYSIS-BULLOSA SIMPLEX; ARRHYTHMOGENIC CARDIOMYOPATHY; ATRIOVENTRICULAR-BLOCK; MUSCULAR-DYSTROPHY; INSERTION MUTATION; MISSENSE MUTATION; DIAGNOSTIC-TEST; GENE-MUTATIONS; ROD DOMAIN; DESMOPLAKIN Multiple languages Cardiac & Cardiovascular Systems; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47136