In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations

Gaertner A, Klauke B, Stork I, Niehaus K, Niemann G (2012)
PloS one 7(10).

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Abstract
BACKGROUND: Although numerous sequence variants in desmoglein-2 (DSG2) have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), the functional impact of new sequence variations is difficult to estimate. METHODOLOGY/PRINCIPAL FINDINGS: To test the functional consequences of DSG2-variants, we established an expression system for the extracellular domain and the full-length DSG2 using the human cell line HT1080. We established new tools to investigate ARVC-associated DSG2 variations and compared wild-type proteins and proteins with one of the five selected variations (DSG2-p.R46Q, -p.D154E, -p.D187G, -p.K294E, -p.V392I) with respect to prodomain cleavage, adhesion properties and cellular localisation. CONCLUSIONS/SIGNIFICANCE: The ARVC-associated DSG2-p.R46Q variation was predicted to be probably damaging by bioinformatics tools and to concern a conserved proprotein convertase cleavage site. In this study an impaired prodomain cleavage and an influence on the DSG2-properties could be demonstrated for the R46Q-variant leading to the classification of the variant as a potential gain-of-function mutant. In contrast, the variants DSG2-p.K294E and -p.V392I, which have an arguable impact on ARVC pathogenesis and are predicted to be benign, did not show functional differences to the wild-type protein in our study. Notably, the variants DSG2-p.D154E and -p.D187G, which were predicted to be damaging by bioinformatics tools, had no detectable effects on the DSG2 protein properties in our study.
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Gaertner A, Klauke B, Stork I, Niehaus K, Niemann G. In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations. PloS one. 2012;7(10).
Gaertner, A., Klauke, B., Stork, I., Niehaus, K., & Niemann, G. (2012). In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations. PloS one, 7(10).
Gaertner, A., Klauke, B., Stork, I., Niehaus, K., and Niemann, G. (2012). In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations. PloS one 7.
Gaertner, A., et al., 2012. In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations. PloS one, 7(10).
A. Gaertner, et al., “In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations”, PloS one, vol. 7, 2012.
Gaertner, A., Klauke, B., Stork, I., Niehaus, K., Niemann, G.: In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations. PloS one. 7, (2012).
Gaertner, Anna, Klauke, Baerbel, Stork, Ines, Niehaus, Karsten, and Niemann, Gesa. “In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations”. PloS one 7.10 (2012).
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