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Sudden infant death syndrome in mice with an inherited mutation in RyR2.

ABSTRACT: Mutations in the cardiac ryanodine receptor gene (RyR2) have been recently identified in victims of sudden infant death syndrome. The aim of this study was to determine whether a gain-of-function mutation in RyR2 increases the propensity to cardiac arrhythmias and sudden death in young mice.Incidence of sudden death was monitored prospectively in heterozygous knock-in mice with mutation R176Q in RyR2 (R176Q/+). Young R176Q/+ mice exhibited a higher incidence of sudden death compared with wild-type littermates. Optical mapping of membrane potentials and intracellular calcium in 1- to 7-day-old R176Q/+ and wild-type mice revealed an increased incidence of ventricular ectopy and spontaneous calcium releases in neonatal R176Q/+ mice. Surface ECGs in 3- to 10-day-old mice showed that R176Q/+ mice developed more ventricular arrhythmias after provocation with epinephrine and caffeine. Intracardiac pacing studies in 12- to 18-day-old mice revealed the presence of an arrhythmogenic substrate in R176Q/+ compared with wild-type mice. Reverse transcription-polymerase chain reaction and Western blotting showed that expression levels of other calcium handling proteins were unaltered, suggesting that calcium leak through mutant RyR2 underlies arrhythmogenesis and sudden death in young R176Q/+ mice.Our findings demonstrate that a gain-of-function mutation in RyR2 confers an increased risk of cardiac arrhythmias and sudden death in young mice and that young R176Q/+ mice may be used as a model for elucidating the complex interplay between genetic and environmental risk factors associated with sudden infant death syndrome.

SUBMITTER: Mathur N

PROVIDER: S-EPMC2796595 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Sudden infant death syndrome in mice with an inherited mutation in RyR2.

Mathur Nitin N Sood Subeena S Wang Sufen S van Oort Ralph J RJ Sarma Satyam S Li Na N Skapura Darlene G DG Bayle J Henri JH Valderrábano Miguel M Wehrens Xander H T XH

Circulation. Arrhythmia and electrophysiology 20091201 6

<h4>Background</h4>Mutations in the cardiac ryanodine receptor gene (RyR2) have been recently identified in victims of sudden infant death syndrome. The aim of this study was to determine whether a gain-of-function mutation in RyR2 increases the propensity to cardiac arrhythmias and sudden death in young mice.<h4>Methods and results</h4>Incidence of sudden death was monitored prospectively in heterozygous knock-in mice with mutation R176Q in RyR2 (R176Q/+). Young R176Q/+ mice exhibited a higher ...[more]

PMID: 20009080

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Project description:Background: Sudden infant death syndrome (SIDS) is one of the leading causes of infant mortality in the United States (US). The extent to which SIDS manifests with an underlying neuropathological mechanism is highly controversial. SIDS correlates with markers of poor prenatal and postnatal care, generally rooted in the lack of access and quality of healthcare endemic to select racial and ethnic groups, and thus can be viewed in the context of health disparities. However, some evidence suggests that at least a subset of SIDS cases may result from a neuropathological mechanism. To explain these issues, a triple-risk hypothesis has been proposed, whereby an underlying biological abnormality in an infant facing an extrinsic risk during a critical developmental period SIDS is hypothesized to occur. Each SIDS decedent is thus thought to have a unique combination of these risk factors leading to their death. This article reviews the neuropathological literature of SIDS and uses machine learning tools to identify distinct subtypes of SIDS decedents based on epidemiological data. Methods: We analyzed US Period Linked Birth/Infant Mortality Files from 1990 to 2017 (excluding 1992–1994). Using t-SNE, an unsupervised machine learning dimensionality reduction algorithm, we identified clusters of SIDS decedents. Following identification of these groups, we identified changes in the rates of SIDS at the state level and across three countries. Results: Through t-SNE and distance based statistical analysis, we identified three groups of SIDS decedents, each with a unique peak age of death. Within the US, SIDS is geographically heterogeneous. Following this, we found low birth weight and normal birth weight SIDS rates have not been equally impacted by implementation of clinical guidelines. We show that across countries with different levels of cultural heterogeneity, reduction in SIDS rates has also been distinct between decedents with low vs. normal birth weight. Conclusions: Different epidemiological and extrinsic risk factors exist based on the three unique SIDS groups we identified with t-SNE and distance based statistical measurements. Clinical guidelines have not equally impacted the groups, and normal birth weight infants comprise more of the cases of SIDS even though low birth weight infants have a higher SIDS rate.

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Sudden infant death syndrome in mice with an inherited mutation in RyR2.

Publications

Sudden infant death syndrome in mice with an inherited mutation in RyR2.

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