Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias

Park, David; Cerrone, Marina; Morley, Gregory E.; Vásquez, Carolina; Fowler, Steven J.; Liu, Nian; Bernstein, Scott; Liu, Fang Yu; Zhang, Jie; Rogers, Christopher S.; Priori, Silvia G.; Chinitz, Larry A.; Fishman, Glenn I.

doi:10.1172/jci76919

Cited by 99 publications

(77 citation statements)

References 45 publications

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“…Volume 125 Number 1 January 2015 transient outward current amplitude (16) and/or on sodium current, as shown in the present study (8).…”

Section: Bringing Home the Baconsupporting

confidence: 82%

“…Gender also contributes to the presentation of BrS: evaluation of a large family with an SCN5A mutation that resulted in nonfunctional sodium channels showed BrS-associated signs only in males that carried the mutant allele (4 of 7), whereas all 6 female SCN5A mutant carriers presented with conduction disease only (15). Park and colleagues analyzed their ECG data only in female animals, although females within the patient study were prone to conduction disease only, not BrS (8). In the male pigs studied, the results were apparently similar to those in females (D. Park and G. Fishman, unpublished observation).…”

Section: Discussionmentioning

confidence: 71%

“…After flecainide administration, the ECG of this patient was more or less consistent with BrS type 1 (8).…”

Section: Discussionmentioning

confidence: 73%

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Bringing home the bacon? The next step in cardiac sodium channelopathies

Wilde¹,

Postema²

2014

J. Clin. Invest.

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“…Volume 125 Number 1 January 2015 transient outward current amplitude (16) and/or on sodium current, as shown in the present study (8).…”

Section: Bringing Home the Baconsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 71%

See 1 more Smart Citation

Bringing home the bacon? The next step in cardiac sodium channelopathies

Wilde¹,

Postema²

2014

J. Clin. Invest.

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“…1B). A similar approach has been used to target porcine CFTR, LDLR, TP53 and SCN5A (29)(30)(31)(32). Following antibiotic selection and PCR screening, ATM +/− clones were used for SCNT to generate ATM +/− piglets.…”

Section: Engineering Of At Pigsmentioning

confidence: 99%

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

et al. 2015

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Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the linkage of ATM with AT onset, the mechanisms linking ATM to neurodegeneration remain undetermined, hindering therapeutic development. Several murine models of AT have been successfully generated showing some of the clinical manifestations of the disease, however they do not fully recapitulate the hallmark neurological phenotype, thus highlighting the need for a more suitable animal model. We engineered a novel porcine model of AT to better phenocopy the disease and bridge the gap between human and current animal models. The initial characterization of AT pigs revealed early cerebellar lesions including loss of Purkinje cells (PCs) and altered cytoarchitecture suggesting a developmental etiology for AT and could advocate for early therapies for AT patients. In addition, similar to patients, AT pigs show growth retardation and develop motor deficit phenotypes. By using the porcine system to model human AT, we established the first animal model showing PC loss and motor features of the human disease. The novel AT pig provides new opportunities to unmask functions and roles of ATM in AT disease and in physiological conditions. † These authors contributed equally.

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“…In a recent study, Park et al attempted to mimic Brugada syndrome phenotype in Yucatan minipigs by heterozygous expression of a nonsense mutation in SCN5A (E558X) identified in a child with Brugada syndrome [Park 2015]. Myocytes isolated from the SCN5A E558X/+ pigs showed a loss of function of INa.…”

Section: Iv14 Limitations Of the Studymentioning

confidence: 99%

Cellular mechanisms underlying the effects of cilostazol, milrinone, isoproterenol and ajmaline on electrographic and arrhythmic manifestations of early repolarization syndrome, and comparative analysis of the cardiac electrophysiological effects of the optical isomers of mexiletine

Patocskai¹

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Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias

Cited by 99 publications

References 45 publications

Bringing home the bacon? The next step in cardiac sodium channelopathies

Bringing home the bacon? The next step in cardiac sodium channelopathies

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

Cellular mechanisms underlying the effects of cilostazol, milrinone, isoproterenol and ajmaline on electrographic and arrhythmic manifestations of early repolarization syndrome, and comparative analysis of the cardiac electrophysiological effects of the optical isomers of mexiletine

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