title: A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill.
abstract: 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 (A-->G). Eight relatives were homozygous for both polymorphisms, which occurred in only approximately 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.
authors.affiliation: Department of Medical Physiology, University Medical Center, Utrecht, The Netherlands.
authors.forename: W Antoinette
authors.initials: WA
authors.lastname: Groenewegen
authors.forename: Mehran
authors.initials: M
authors.lastname: Firouzi
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Saskia
authors.initials: S
authors.lastname: Vliex
authors.forename: Irene M
authors.initials: IM
authors.lastname: van Langen
authors.forename: Lodewijk
authors.initials: L
authors.lastname: Sandkuijl
authors.forename: Jeroen P P
authors.initials: JP
authors.lastname: Smits
authors.forename: Miriam
authors.initials: M
authors.lastname: Hulsbeek
authors.forename: Martin B
authors.initials: MB
authors.lastname: Rook
authors.forename: Habo J
authors.initials: HJ
authors.lastname: Jongsma
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D016275:Atrial Function / Q000235:genetics*; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004244:Dizziness / Q000209:etiology; D004562:Electrocardiography; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009426:Netherlands; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013575:Syncope / Q000209:etiology; D014162:Transfection; D014982:Xenopus laevis; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels; D000097003:Gap Junction alpha-5 Protein; C568320:SCN5A protein, human