Identification of a gene responsible for familial Wolff-Parkinson-White syndrome
Open accessAbstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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New data on the genetics of supraventricular tachycardia continually appear since the identification of a missense mutation in PRKAG2 as a cause of familial Wolff-Parkinson-White syndrome.
“New data on the genetics of SVT continually appear since the identification of a missense mutation in the gene PRKAG2, that encodes the regulatory g-subunit of AMP-activated protein kinase, as a cause of familial Wolff -Parkinson -White syndrome.429,430”
From European Heart Rhythm Association (EHRA) consensus document on the management of supraventricular arrhythmias, endorsed by Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLAECE) (2017) · cites this paper as [429]
Point mutations in conserved residues within CBS domains cause several hereditary human diseases, including homocystinuria, retinitis pigmentosa, congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, classic Bartter syndrome, and Wolff-Parkinson-White syndrome.
“mutations in conserved residues within them cause a variety of human hereditary diseases, including (with the gene mutated in parentheses): Wolff-Parkinson-White syndrome ( γ 2 subunit of AMP-activated protein kinase); retinitis pigmentosa (IMP dehydrogenase-1); congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel”
From CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations (2004) · cites this paper as [10]
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- Authors
- Gollob, M. H., Green, M. S., Tang, A. S.-L., Gollob, T., Karibe, A., Hassan, A.-S., Ahmad, F., Lozado, R., Shah, G., Fananapazir, L., Bachinski, L. L., Tapscott, T., Gonzales, O., Begley, D., Mohiddin, S., & Roberts, R.
- Affiliations
- Baylor College of Medicine (US)
- Ottawa Heart Institute (CA)
- National Institutes of Health (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2001-06-14
- Volume
- 344
- Issue
- 24
- Pages
- 1823-1831
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2324797060
- Cited by
- 671
- References
- 25
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 18 · 2023: 15 · 2022: 26 · 2021: 17 · 2020: 23 · 2019: 17 · 2018: 20 · 2017: 15 · 2016: 35 · 2015: 18 · 2014: 15 · 2013: 24 · 2012: 38
- FWCI
- 28.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Arrhythmias and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- PRKAG2, missense mutations, preexcitation, genetic linkage, haplotype analysis, autosomal dominant inheritance, supraventricular arrhythmias, sudden cardiac death, cardiac hypertrophy
- MeSH terms
- Base Sequence, Chromosome Mapping, Chromosomes, Human, Pair 7, Female, Genes, Dominant, Haplotypes, Humans, Lod Score, Male, Multienzyme Complexes, Pedigree, Wolff-Parkinson-White Syndrome, Protein Serine-Threonine Kinases, Mutation, Missense, AMP-Activated Protein Kinases
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