Volume 7, Issue 10, Pages (October 2010)

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Date of download: 7/7/2016 Copyright © The American College of Cardiology. All rights reserved. From: Tcap gene mutations in hypertrophic cardiomyopathy.

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Volume 7, Issue 10, Pages 1446-1453 (October 2010) Novel missense mutations in exon 15 of desmoglein-2: Role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy? Katja Gehmlich, PhD, Angeliki Asimaki, PhD, Thomas J. Cahill, MA, MRCP, Elisabeth Ehler, PhD, Petros Syrris, PhD, Elisabetta Zachara, MD, Federica Re, MD, Andrea Avella, MD, Lorenzo Monserrat, MD, Jeffrey E. Saffitz, MD, PhD, William J. McKenna, MD, FRCP Heart Rhythm Volume 7, Issue 10, Pages 1446-1453 (October 2010) DOI: 10.1016/j.hrthm.2010.08.007 Copyright © 2010 Heart Rhythm Society Terms and Conditions

Figure 1 Identification of novel mutations in DSG2 exon 15. A: Pedigree of family A with a heterozygous DSG2 G812S mutation. Black symbols indicate individuals fulfilling diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC)1; white symbols indicate individuals who do not fulfill task force criteria; gray symbol indicates borderline ARVC diagnosis; black and white symbol indicates sudden cardiac death at age 42 years. Slanted bars indicate deceased individuals; squares indicate males; circles indicate females; plus and minus signs indicate presence or absence of DSG2 mutation, respectively; arrow indicates index patient. n.d. = individual not available for clinical evaluation. For details of the clinical evaluation, see Table 1. B: Pedigree of family B with a heterozygous DSG2 C813R mutation. Symbols as in panel A. C: Sequence electropherogram of the G→A change at nucleotide position c. 2434 (open arrow in individual A.1) compared to a normal wild-type (WT) individual (A.8). D: Sequence electropherogram of the T→C change at nucleotide position c. 2437 (open arrow in individual B.1) compared to a normal WT individual (B.2). Heart Rhythm 2010 7, 1446-1453DOI: (10.1016/j.hrthm.2010.08.007) Copyright © 2010 Heart Rhythm Society Terms and Conditions

Figure 2 Confocal immunofluorescence microscopy analysis of control and gene-positive right ventricular myocardium (individuals A.1 and A.3; see Figure 1) showing the amount of immunoreactive signal for selected junctional proteins at intercalated disks. Scale bars (bottom left) = 10 μm. Heart Rhythm 2010 7, 1446-1453DOI: (10.1016/j.hrthm.2010.08.007) Copyright © 2010 Heart Rhythm Society Terms and Conditions

Figure 3 Mutations in the desmoglein-2 (DSG2) intracellular cadherin segment (ICS) domain. A: Position of the mutations in DSG2. (Modified from Awad et al.3) The proteolytic cleavage site (scissors symbol), the five extracellular cadherin domains (EC), the transmembrane region (TM), and the location of the ICS domain within the cytoplasmic portion are indicated. Sequence alignment of the ICS domain for desmosomal cadherin demonstrates conservation of the affected amino acids G812 and C813 (asterisks).B: Binding of plakoglobin (PG) and plakophilin-2 (PKP2) to DSG2 ICS wild-type (WT) in glutathione-S-transferase (GST) pulldown assays. A 1% input dilution of the rat heart lysate and GST-fusion protein input, together with GST alone control, are shown (position of marker proteins is indicated on the right). Multiple bands below 50 kD in lane 1 are due to partial degradation of DSG2 ICS in vitro.C: In binding experiments similar to those shown in panel B, the binding of the three DSG2 mutations was tested in comparison to DSG2 ICS WT. No changes were observed in binding of PG and PKP2. The abnormal migration of DSG2 C813R is marked with an arrow.D: Binding experiments with GST fusion proteins expressed in mammalian COS-1 cells. Binding to PG was normal for all three mutants tested, whereas binding to PKP2 was below the detection limit. Arrow as in panel C. E: Altered electrophoretic mobility of DSG2 ICS C813R in comparison to the WT protein fragment. A DSG2 ICS C813A mutation restores normal migration properties. Heart Rhythm 2010 7, 1446-1453DOI: (10.1016/j.hrthm.2010.08.007) Copyright © 2010 Heart Rhythm Society Terms and Conditions

Figure 4 Localization of the three desmoglein-2 (DSG2) mutant proteins at the intercalated disk of cardiomyocytes. Green fluorescent protein (GFP) fusion proteins of DSG2 wild-type (WT) and the three mutants were transiently expressed in NRC. Intercalated disks were visualized by counterstaining for beta-catenin. Nuclei were visualized with 4′,6-diamidino-2-phenylindole (DAPI). Merged images: DSG2-GFP green, beta-catenin red, DAPI blue. Scale bar = 10 μm. Heart Rhythm 2010 7, 1446-1453DOI: (10.1016/j.hrthm.2010.08.007) Copyright © 2010 Heart Rhythm Society Terms and Conditions