Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease
Vincent Probst, MD*,
Florence Kyndt, PharmD, PhD ,
Franck Potet, MBs,
Jean-Noel Trochu, MD*,
Guy Mialet, MD ,
Sophie Demolombe, PhD,
Jean-Jacques Schott, PhD,
Isabelle Baró, PhD,
Denis Escande, MD, PhD,* and
Hervé Le Marec, MD, PhD*
* Cardiology Department, Hôpital G&R Laennec, Nantes, France
Institut National de la Santé et de la Recherche Médicale (INSERM) U533, Faculté de Médecine, Nantes, France
Centre Hospitalier de La Roche/Yon, France
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Figure 1 Pedigree of the four-generation family with progressive cardiac conduction defect. Filled symbols = patients carrying the mutation or obligate carriers; open symbols = noncarriers. PM = patients with a pacemaker.
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Figure 2 Examples of electrocardiogram patterns in affected members. Patient II-19 was a 70-year-old woman with parietal block and left-axis deviation (heart rate [HR]: 64 beats/min, P: 144 ms, PR: 215 ms, QRS: 160 ms). A pacemaker was implanted because of several episodes of syncope. Patient III-2 was a 49-year-old man with a parietal block and undetermined axis (HR: 54 beats/min, P: 150 ms, PR: 244 ms, QRS 128 ms). Patient III-31 was a 48-year-old woman with right bundle branch block (HR: 64 beats/min, P: 153 ms, PR: 205 ms, QRS: 172 ms). Sudden widening of QRS complexes and occurrence of 2-1 atrioventricular block during exercise led to pacemaker implantation. Patient II-20 was a 78-year-old woman with left bundle branch block (HR: 59 beats/min, P: 157 ms, PR: 248 ms, QRS: 196 ms). A pacemaker was implanted after two episodes of syncope.
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Figure 3 Averaged electrocardiogram parameters in noncarriers (white bars) and in gene carriers (black bars). *Statistical significance. HR = heart rate.
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Figure 4 Serial electrocardiograms performed in Patient III-31 showing progressive development of conduction defect. Electrocardiograms recorded in 1982, 1998, and 2000 show progressive increase in QRS duration (QRS: 130, 140, and 172 ms).
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Figure 5 Evolution with aging of conduction parameters in affected (filled symbols) and unaffected subjects (open symbols). (A) Averaged and filtered P-wave duration. (B) PR duration. (C) QRS duration. In A and B, data were fitted with a linear regression analysis. In C, assessment of the residuals showed that the linear model was poorly adapted to fit the relation between QRS duration and aging in affected members. The variance was significantly different before and after the age of 40 (ratio variance test; p < 0.001). This was indicative of a threshold effect of age. Two linear regression analyses were thus performed before and after the age of 40.
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Figure 6 Exon trapping amplification and sequence analysis of splice product. (A) Reverse transcription-polymerase chain reaction (PCR) amplification products derived from the exon-trapping experiment and revealed on a 1.7% TBE agarose gel. Mutated: PCR fragment corresponding to the exon 22 skipped transcript (209 bp). WT = wild-type transcript (332 bp). (B) Sequence analysis of the 209 bp splice product confirms exon 22 skipping in the mutant allele.
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exon 22-SCN5A (C and D) in the absence (A and C) or presence (B and D) of the beta-1 regulatory subunit. Holding potential: –100 mV. Depolarizing steps from –60 mV to +30 mV in 10 mV increments. Vertical bar = 0.5 nA. Horizontal bar = 5 ms. (E) Membrane trafficking of GFP-tagged wild-type (WT) or exon 22 deleted (