Mutations of the Cardiac Ryanodine Receptor (RyR2) Gene in Familial Polymorphic Ventricular Tachycardia
Open accessAbstract
Background—Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of ≈30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]). Methods and Results—In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders. Conclusions—Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.
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In patients with CPVT, 60% have a mutation in either RyR2 or CASQ2.
“In patients with CPVT, 60% have a mutation in either the gene encoding the cardiac ryanodine receptor (RyR2) (autosomal dominant) or in the cardiac calsequestrin gene (CASQ2) (autosomal recessive) (330–333).”
From 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope (2017) · cites this paper as [331]
The Results section, “Identification of 3 Missense Mutations in the RyR2 Gene in 3 Different Families” (page not provided), reports RyR2 mutations in three of four studied families. This supports RyR2 as a cause of familial polymorphic ventricular tachycardia, but the paper does not establish that 60% of patients with CPVT have an RyR2 or CASQ2 mutation, and the passages do not address CASQ2. (LLM, conf=0.88)
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- Authors
- Laitinen, P. J., Brown, K. M., Piippo, K., Swan, H., Devaney, J. M., Brahmbhatt, B., Donarum, E. A., Marino, M., Tiso, N., Viitasalo, M., Toivonen, L., Stephan, D. A., & Kontula, K.
- Affiliations
- From the Department of Medicine, University of Helsinki, Helsinki, Finland (P.J.L., K.P., H.S., M.V., L.T., K.K.); the Research Center for Genetic Medicine, Children’s National Medical Center, Washington, DC (K.M.B., B.B., E.A.D., D.A.S.); the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD (K.M.B., D.A.S.); Transgenomic, Inc, Gaithersburg, MD (J.M.D., M.M.); and the Department of Biology, University of Padova, Padova, Italy (N.T.).
- National Institutes of Health (US)
- Venue
- Circulation
- Published
- 2001-01-30
- Volume
- 103
- Issue
- 4
- Pages
- 485-490
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2100477955
- Cited by
- 726
- References
- 32
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 13 · 2023: 5 · 2022: 27 · 2021: 22 · 2020: 18 · 2019: 24 · 2018: 14 · 2017: 29 · 2016: 24 · 2015: 20 · 2014: 24 · 2013: 41 · 2012: 41
- FWCI
- 27.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- other-oa
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, other-oa)
- Funders
- American Heart Association
- Foundation for Cardiovascular Research
- Biomedicum Helsinki-säätiö
- Sydäntutkimussäätiö
- National Institutes of Health
- National Human Genome Research Institute
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Keywords
- RyR2, RyR2 mutations, missense mutations, sarcoplasmic reticulum calcium release channel, inherited arrhythmia, co-segregation, single nucleotide polymorphisms
- MeSH terms
- Base Sequence, Chromosome Mapping, Chromosomes, Human, Pair 1, DNA, DNA Mutational Analysis, Family Health, Female, Finland, Haplotypes, Humans, Male, Mutation, Myocardium, Pedigree, Polymorphism, Genetic, Tachycardia, Ventricular, Microsatellite Repeats, Ryanodine Receptor Calcium Release Channel, Mutation, Missense
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