Back to Search
Start Over
A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill
- Source :
- Circulation research, 92(1), 14-22. LIPPINCOTT WILLIAMS & WILKINS, Circulation research, 92(1), 14-22. Lippincott Williams and Wilkins
- Publication Year :
- 2003
-
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.
- Subjects :
- Male
Candidate gene
Patch-Clamp Techniques
Physiology
DNA Mutational Analysis
gap junction protein
sinus arrest
Gene mutation
Connexins
Sodium Channels
NAV1.5 Voltage-Gated Sodium Channel
Electrocardiography
Xenopus laevis
connexin 40
Gap junction channel
Genotype
genetic polymorphism
gene mutation
familial disease
heart depolarization
Netherlands
Genetics
Regulation of gene expression
Sodium channel
Genetic disorder
article
sodium ion
gene expression regulation
Atrial Function
reporter gene
Pedigree
Phenotype
priority journal
Mutation (genetic algorithm)
Female
Cardiology and Cardiovascular Medicine
Arrhythmia
gene segregation
Adult
medicine.medical_specialty
scn5a gene
Adolescent
heart arrhythmia
tissue specificity
Biology
Transfection
Dizziness
Syncope
gap junction
arrhythmogenesis
Internal medicine
Obligate carrier
medicine
Animals
Humans
human
Polymorphism
Gene
Aged
Polymorphism, Genetic
nucleotide sequence
Arrhythmias, Cardiac
gene structure
medicine.disease
Endocrinology
Amino Acid Substitution
Mutation
Oocytes
genetic disorder
Subjects
Details
- ISSN :
- 15244571 and 00097330
- Volume :
- 92
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Circulation research
- Accession number :
- edsair.doi.dedup.....a21ef8e68892b630ffc1bcae835a8f94