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      Molecular Genetic Studies in Atrial Fibrillation

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          Atrial fibrillation is a complex disease. Its etiologies are diverse and genetic factors may also contribute to this disease. With the advent of modern molecular biology technology, it is now possible to explore the genetic components in the pathogenesis of atrial fibrillation. Past molecular genetic studies on atrial fibrillation in the literature can be divided into linkage analysis studies and association studies. The subjects for linkage analysis studies are pedigrees of probands with Mendelian hereditary atrial fibrillation. The first locus identified for autosomal dominant atrial fibrillation locates at 10q22–q24. However, the exact gene is still unknown. Another linkage analysis study in Chinese revealed that LQT1 gene (I<sub>Ks</sub> α-subunit) was the responsible gene. A missense mutation in the I<sub>Ks</sub> α-subunit results in a gain of function, which is important in causing atrial fibrillation. The third known locus for familial atrial fibrillation locates at 6q14–16. The responsible gene remains still unknown. The other type of studies takes the case-control design (association studies) and the subjects have multigenic atrial fibrillation. In a study in a Japanese population, it was reported that the angiotensin-converting enzyme insertion/deletion polymorphism was not associated with atrial fibrillation. On the other hand, researchers in Taiwan reported that a nonsynonymous single nucleotide polymorphism of the LQT5 gene (I<sub>Ks</sub> β-subunit) is associated with atrial fibrillation. In summary, there is growing evidence showing that genetic factors are important in the pathogenesis of atrial fibrillation. We expect that more genes responsible for or contributing to atrial fibrillation will be identified in the future and these will elucidate the molecular mechanisms of atrial fibrillation.

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          Most cited references 11

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          KCNQ1 gain-of-function mutation in familial atrial fibrillation.

          Atrial fibrillation (AF) is a common cardiac arrhythmia whose molecular etiology is poorly understood. We studied a family with hereditary persistent AF and identified the causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome 11p15.5. The KCNQ1 gene encodes the pore-forming alpha subunit of the cardiac I(Ks) channel (KCNQ1/KCNE1), the KCNQ1/KCNE2 and the KCNQ1/KCNE3 potassium channels. Functional analysis of the S140G mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and the KCNQ1/KCNE2 currents, which contrasts with the dominant negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome. Thus, the S140G mutation is likely to initiate and maintain AF by reducing action potential duration and effective refractory period in atrial myocytes.
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            Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.

            Mutations in ion channels involved in the generation and termination of action potentials constitute a family of molecular defects that underlie fatal cardiac arrhythmias in inherited long-QT syndrome. We report here that a loss-of-function (E1425G) mutation in ankyrin-B (also known as ankyrin 2), a member of a family of versatile membrane adapters, causes dominantly inherited type 4 long-QT cardiac arrhythmia in humans. Mice heterozygous for a null mutation in ankyrin-B are haploinsufficient and display arrhythmia similar to humans. Mutation of ankyrin-B results in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins), which reduces the targeting of these proteins to the transverse tubules as well as reducing overall protein level. Ankyrin-B mutation also leads to altered Ca2+ signalling in adult cardiomyocytes that results in extrasystoles, and provides a rationale for the arrhythmia. Thus, we identify a new mechanism for cardiac arrhythmia due to abnormal coordination of multiple functionally related ion channels and transporters.
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              Identification of a gene responsible for familial Wolff-Parkinson-White syndrome.

              The Wolff-Parkinson-White syndrome, with a prevalence in Western countries of 1.5 to 3.1 per 1000 persons, causes considerable morbidity and may cause sudden death. We identified two families in which the Wolff-Parkinson-White syndrome segregated as an autosomal dominant disorder. We studied 70 members of the two families (57 in Family 1 and 13 in Family 2). The subjects underwent 12-lead electrocardiography and two-dimensional echocardiography. Genotyping mapped the gene responsible to 7q34-q36, a locus previously identified to be responsible for an inherited form of Wolff-Parkinson-White syndrome. Candidate genes were identified, sequenced, and analyzed in normal and affected family members to identify the disease-causing gene. A total of 31 members (23 from Family 1 and 8 from Family 2) had the Wolff-Parkinson-White syndrome. Affected members of both families had ventricular preexcitation with conduction abnormalities and cardiac hypertrophy. The maximal combined two-point lod score was 9.82 at a distance of 5 cM from marker D7S636, which confirmed the linkage of the gene in both families to 7q34-q36. Haplotype analysis indicated that there were no alleles in common in the two families at this locus, suggesting that the two families do not have a common founder. We identified a missense mutation in the gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase (PRKAG2). The mutation results in the substitution of glutamine for arginine at residue 302 in the protein. The identification of this genetic defect has important implications for elucidating the pathogenesis of ventricular preexcitation. Further understanding of how this molecular defect leads to supraventricular arrhythmias could influence the development of specific therapies for other forms of supraventricular arrhythmia.

                Author and article information

                S. Karger AG
                November 2003
                21 November 2003
                : 100
                : 3
                : 109-113
                aInstitute of Pharmacology, National Taiwan University, bDepartment of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; cDivision of Cardiology, Texas Technical University Health Sciences Center, Lubbock, Tex., USA
                73910 Cardiology 2003;100:109–113
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 1, References: 28, Pages: 5


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