A Cardiac Sodium Channel Mutation Cosegregates With a Rare Connexin40 Genotype in Familial Atrial Standstill by W. Antoinette Groenewegen, Mehran Firouzi,

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A Cardiac Sodium Channel Mutation Cosegregates With a Rare Connexin40 Genotype in Familial Atrial Standstill by W. Antoinette Groenewegen, Mehran Firouzi, Connie R. Bezzina, Saskia Vliex, Irene M. van Langen, Lodewijk Sandkuijl, Jeroen P.P. Smits, Miriam Hulsbeek, Martin B. Rook, Habo J. Jongsma, and Arthur A.M. Wilde Circulation Research Volume 92(1):14-22 January 10, 2003 Copyright © American Heart Association, Inc. All rights reserved.

Figure 1. Pedigree of the Dutch AS family. Figure 1. Pedigree of the Dutch AS family. Open circles and squares indicate unaffected women and men; closed circles and squares, affected women and men; and hatched, filled symbols, clinical status unknown. Only those individuals for which ECG and/or blood was available for the study are numbered. The arrow indicates the proband. The genotypes below each person’s symbol are, from top to bottom, as follows: Cx40 −44-bp polymorphism (rare AA in bold), Cx40 +71-bp polymorphism (rare GG in bold), and SCN5A-D1275N mutation status, where MT indicates heterozygous D1275N (bold); WT, wild type; and boxed genotype, concurrence of rare Cx40 genotypes and SCN5A mutation. W. Antoinette Groenewegen et al. Circ Res. 2003;92:14-22 Copyright © American Heart Association, Inc. All rights reserved.

Figure 2. Selected ECGs from AS family. Figure 2. Selected ECGs from AS family. The ECGs of the proband (III-16), her father (II-10), and his cousin (II-4) show absence of atrial activity and narrow QRS complex escape rhythm (III-16 and II-10) or ventricular escape rhythm (II-4). The narrow QRS complex escape rhythm presumably originates from the AV node or upper specialized conduction system. For comparison, a normal sinus rhythm ECG of the sister of the proband (III-15) is shown. W. Antoinette Groenewegen et al. Circ Res. 2003;92:14-22 Copyright © American Heart Association, Inc. All rights reserved.

Figure 3. Identification of SCN5A mutation D1275N. Figure 3. Identification of SCN5A mutation D1275N. A, Sequence electropherograms around SCN5A amino acid residue 1275 in control and proband. The arrow indicates the homozygous G nucleotide in the control or the heterozygous A/G nucleotides in the proband. B, TaqI restriction digest of individuals with the shared SCN5A haplotype. The lower band indicates wild-type chromosome; upper band, presence of D1275N mutation. Part of the pedigree from Figure 1 is shown. For explanation of pedigree symbols, see Figure 1. Lane M indicates marker (specific sizes for two marker bands are given). Individual III-7 was included as a control to confirm complete TaqI digestion of the PCR products. W. Antoinette Groenewegen et al. Circ Res. 2003;92:14-22 Copyright © American Heart Association, Inc. All rights reserved.

Figure 4. Sequence electropherograms for the Cx40 polymorphisms. Figure 4. Sequence electropherograms for the Cx40 polymorphisms. Left, Polymorphism at position −44 bp. Right, Polymorphism at position +71 bp. For each polymorphism, sequences for all three possible genotypes are shown. The middle sequence in each column was obtained in the proband. W. Antoinette Groenewegen et al. Circ Res. 2003;92:14-22 Copyright © American Heart Association, Inc. All rights reserved.

Figure 5. A, Macroscopic current traces generated by wild-type or D1275N channels in the absence or presence of hβ1 as indicated. Figure 5. A, Macroscopic current traces generated by wild-type or D1275N channels in the absence or presence of hβ1 as indicated. Sodium currents were stimulated by test potentials from −70 to +40 mV in 5-mV increments from a holding potential of −100 mV. B, Comparison of the voltage dependence of activation and inactivation of wild-type (WT) and D1275N sodium channels in the absence (left) and presence (right) of hβ1. Data were fitted with a Boltzmann equation to estimate the potential for half-maximal activation or inactivation (V1/2) and slope factor (k) (see Table in the online data supplement). V1/2 activation for D1275N channels in the absence of hβ1 was shifted +3.8 mV compared with wild-type channels (P<0.05). No other differences were found. C, Slow component of inactivation. No difference was found between wild-type and D1275N channels either in the absence (left) or presence (right) of hβ1. Data for V1/2, slope factor, and steady-state level of slow inactivation can be found in the online Table, which is available in the data supplement. D, Recovery from inactivation, measured by stepping from VH −100 mV to a test potential of −30 mV, in the absence (left) and presence (right) of hβ1. Tau WT: 32.1±1.65 ms and D1275N: 25.1±1.95 ms (P<0.01); tau WT+hβ1: 20.12±3.19 ms and D1275N+hβ1: 13.95±0.74 ms. W. Antoinette Groenewegen et al. Circ Res. 2003;92:14-22 Copyright © American Heart Association, Inc. All rights reserved.

Figure 6. Effect of Cx40 gene polymorphisms on luciferase gene expression in A7r5 cells. Figure 6. Effect of Cx40 gene polymorphisms on luciferase gene expression in A7r5 cells. Constructs containing either the common human Cx40 haplotype p(−44G,+71A) or the rare human Cx40 haplotype p(−44A,+71G) were tested for luciferase activity. Plasmid p(−175,+85), which contains the equivalent Cx40 rat promoter region previously shown to be active in A7r5 cells, was included for comparison. Results are expressed as fold activity above pGL3-basic luciferase activity levels (set at 1.0) in each experiment. The mean activity level for p(−44G,+71A) from 6 experiments was then set at 100, and the activity levels of the other constructs were expressed relative to p(−44G,+71A). Values are mean±SD (n=6). W. Antoinette Groenewegen et al. Circ Res. 2003;92:14-22 Copyright © American Heart Association, Inc. All rights reserved.

Figure 7. PR interval in AS family Figure 7. PR interval in AS family. “Unaffected family members” indicates individuals without the D1275N mutation or the rare Cx40 genotype. “Unaffected family members with rare Cx40 genotype” indicates individuals without the D1275N mutation but with the rare Cx40 genotype. “Unaffected family members with D1275N mutation” indicates individuals without the rare Cx40 genotype but with the D1275N mutation. “AS patient with both D1275N mutation and rare Cx40 genotype” indicates the genotyped AS patient. Figure 7. PR interval in AS family. “Unaffected family members” indicates individuals without the D1275N mutation or the rare Cx40 genotype. “Unaffected family members with rare Cx40 genotype” indicates individuals without the D1275N mutation but with the rare Cx40 genotype. “Unaffected family members with D1275N mutation” indicates individuals without the rare Cx40 genotype but with the D1275N mutation. “AS patient with both D1275N mutation and rare Cx40 genotype” indicates the genotyped AS patient. For two other genotyped AS patients, no PR interval was available (see text for details). *Significant difference between two groups; values are mean±SEM. W. Antoinette Groenewegen et al. Circ Res. 2003;92:14-22 Copyright © American Heart Association, Inc. All rights reserved.