Published online before print December 5, 2002, doi: 10.1161/01.RES.0000050585.07097.D7
© 2003 American Heart Association, Inc.
Clinical Research |
A Cardiac Sodium Channel Mutation Cosegregates With a Rare Connexin40 Genotype in Familial Atrial Standstill
From the Department of Medical Physiology (W.A.G., M.F., S.V., M.B.R., H.J.J.), University Medical Center, Utrecht, The Netherlands; the Experimental and Molecular Cardiology Group (C.R.B., J.P.P.S., A.A.M.W.) and the Department of Clinical Genetics (C.R.B., I.M.v.L., M.H.), Academic Medical Center, Amsterdam, The Netherlands; and the Department of Medical Statistics (L.S.), Leiden University Medical Center, Leiden, The Netherlands.
Correspondence to A.A.M. Wilde, MD, Department of Medical Physiology, University Medical Center Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands. E-mail A.A.Wilde{at}AMC.UVA.NL
Atrial standstill (AS) is a rare arrhythmia that occasionally appears to be genetically determined. This study investigates the genetic background of this arrhythmogenic disorder in a large family. Forty-four family members were clinically evaluated. One deceased and three living relatives were unambiguously affected by AS. All other relatives appeared unaffected. Candidate gene screening revealed a novel mutation in the cardiac sodium channel gene SCN5A (D1275N) in all three affected living relatives and in five unaffected relatives, and the deceased relative was an obligate carrier. In addition, two closely linked polymorphisms were detected within regulatory regions of the gene for the atrial-specific gap junction protein connexin40 (Cx40) at nucleotides -44 (G
A) and +71 (AG). Eight relatives were homozygous for both polymorphisms, which occurred in only 
7% of control subjects, and three of these relatives were affected by AS. The three living AS patients exclusively coinherited both the rare Cx40 genotype and the SCN5A-D1275N mutation. SCN5A-D1275N channels showed a small depolarizing shift in activation compared with wild-type channels. Rare Cx40 genotype reporter gene analysis showed a reduction in reporter gene expression compared with the more common Cx40 genotype. In this study, familial AS was associated with the concurrence of a cardiac sodium channel mutation and rare polymorphisms in the atrial-specific Cx40 gene. We propose that, although the functional effect of each genetic change is relatively benign, the combined effect of genetic changes eventually progresses to total AS.
Key Words: arrhythmia • sodium channel • mutation • gap junction channel • polymorphism
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