Journal article
Molecular characterization of the calcium release channel deficiency syndrome
JCI insight, Vol.5(15), e135952
08/06/2020
DOI: 10.1172/jci.insight.135952
PMCID: PMC7455073
PMID: 32663189
Abstract
We identified a potentially novel homozygous duplication involving the promoter region and exons 1–4 of the gene encoding type 2 cardiac ryanodine receptor (
RYR2
) that is responsible for highly penetrant, exertion-related sudden deaths/cardiac arrests in the Amish community without an overt phenotype to suggest
RYR2-
mediated catecholaminergic polymorphic ventricular tachycardia (CPVT). Homozygous RYR2 duplication (RYR2-DUP) induced pluripotent stem cell cardiomyocytes (iPSC-CMs) were generated from 2 unrelated patients. There was no difference in baseline Ca
2+
handling measurements between WT-iPSC-CM and RYR2-DUP-iPSC-CM lines. However, compared with WT-iPSC-CMs, both patient lines demonstrated a dramatic reduction in caffeine-stimulated and isoproterenol-stimulated (ISO-stimulated) Ca
2+
transient amplitude, suggesting RyR2 loss of function. There was a greater than 50% reduction in
RYR2
transcript/RyR2 protein expression in both patient iPSC-CMs compared with WT. Delayed afterdepolarization was observed in the RYR2-DUP-iPSC-CMs but not in the WT-iPSC-CMs. Compared with WT-iPSC-CMs, there was significantly elevated arrhythmic activity in the RYR2-DUP-iPSC-CMs in response to ISO. Nadolol, propranolol, and flecainide reduced erratic activity by 8.5-fold, 6.8-fold, and 2.4-fold, respectively, from ISO challenge. Unlike the gain-of-function mechanism observed in
RYR2-
mediated CPVT, the homozygous multiexon duplication precipitated a dramatic reduction in
RYR2
transcription and RyR2 protein translation, a loss of function in calcium handling, and a calcium-induced calcium release apparatus that is insensitive to catecholamines and caffeine.
Molecular and functional characterization of the calcium release channel deficiency syndrome in patient-specific induced pluripotent stem cell-cardiomyocytes.
Details
- Title: Subtitle
- Molecular characterization of the calcium release channel deficiency syndrome
- Creators
- David J. Tester - Mayo ClinicCS John Kim - Mayo Clinic in FloridaSamantha K. Hamrick - Mayo ClinicDan Ye - Mayo ClinicBailey J. O’Hare - Mayo ClinicHannah M. Bombei - Division of Cardiology, University of Iowa Stead Family Children’s Hospital, Iowa City, Iowa, USAKristi K. Fitzgerald - Alfred I. duPont Hospital for ChildrenCarla M. Haglund-Turnquist - Mayo ClinicDianne L. Atkins - Division of Cardiology, University of Iowa Stead Family Children’s Hospital, Iowa City, Iowa, USALuis A. Ochoa Nunez - Division of Cardiology, University of Iowa Stead Family Children’s Hospital, Iowa City, Iowa, USAIan Law - University of IowaJoel Temple - Alfred I. duPont Hospital for ChildrenMichael J. Ackerman - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.5(15), e135952
- DOI
- 10.1172/jci.insight.135952
- PMID
- 32663189
- PMCID
- PMC7455073
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical Investigation
- Grant note
- not applicable / Mayo Clinic not applicable / ;
- Language
- English
- Date published
- 08/06/2020
- Academic Unit
- Cardiology; Stead Family Department of Pediatrics
- Record Identifier
- 9984353846502771
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