Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin-2 mutations.
OBJECTIVE
Recent immunohistochemical studies observed the loss of plakoglobin (PG) from the intercalated disc (ID) as a hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting a final common pathway for this disease. However, the underlying molecular processes are poorly understood.


RESULTS
We have identified novel mutations in the desmosomal cadherin desmocollin 2 (DSC2 R203C, L229X, T275M, and G371fsX378). The two missense mutations (DSC2 R203C and T275M) have been functionally characterized, together with a previously reported frameshift variant (DSC2 A897fsX900), to examine their pathogenic potential towards PG's functions at the ID. The three mutant proteins were transiently expressed in various cellular systems and assayed for expression, processing, localization, and binding to other desmosomal components in comparison to wild-type DSC2a protein. The two missense mutations showed defects in proteolytic cleavage, a process which is required for the functional activation of mature cadherins. In both cases, this is thought to cause a reduction of functional DSC2 at the desmosomes in cardiac cells. In contrast, the frameshift variant was incorporated into cardiac desmosomes; however, it showed reduced binding to PG.


CONCLUSIONS
Despite different modes of action, for all three variants, the reduced ability to provide a ligand for PG at the desmosomes was observed. This is in agreement with the reduced intensity of PG at these structures observed in ARVC patients.
Institute of Cardiovascular Science, University College London, London, UK. katja.gehmlich@cardiov.ox.ac.uk
Katja
K
Gehmlich
Petros
P
Syrris
Emma
E
Peskett
Alison
A
Evans
Elisabeth
E
Ehler
Angeliki
A
Asimaki
Aris
A
Anastasakis
Adalena
A
Tsatsopoulou
Apostolos-Ilias
AI
Vouliotis
Christodoulos
C
Stefanadis
Jeffrey E
JE
Saffitz
Nikos
N
Protonotarios
William J
WJ
McKenna
D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D051187:Desmocollins / Q000235:genetics / Q000378:metabolism*; D003896:Desmosomes / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051381:Rats; D014162:Transfection; D051185:gamma Catenin / Q000378:metabolism
C081561:DSC2 protein, human; D051187:Desmocollins; D008024:Ligands; D051185:gamma Catenin