Citation

BibTex format

@article{Smith:2018:10.1016/j.stemcr.2018.10.006,
author = {Smith, JGW and Owen, T and Bhagwan, JR and Mosqueira, D and Scott, E and Mannhardt, I and Patel, A and Barriales-Villa, R and Monserrat, L and Hansen, A and Eschenhagen, T and Harding, SE and Marston, S and Denning, C},
doi = {10.1016/j.stemcr.2018.10.006},
journal = {Stem Cell Reports},
pages = {1226--1243},
title = {Isogenic pairs of hiPSC-CMs with hypertrophic cardiomyopathy/LVNC-associated ACTC1 E99K mutation unveil differential functional deficits},
url = {http://dx.doi.org/10.1016/j.stemcr.2018.10.006},
volume = {11},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Hypertrophic cardiomyopathy (HCM) is a primary disorder of contractility in heart muscle. To gain mechanistic insight and guide pharmacological rescue, this study models HCM using isogenic pairs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the E99K-ACTC1 cardiac actin mutation. In both 3D engineered heart tissues and 2D monolayers, arrhythmogenesis was evident in all E99K-ACTC1 hiPSC-CMs. Aberrant phenotypes were most common in hiPSC-CMs produced from the heterozygote father. Unexpectedly, pathological phenotypes were less evident in E99K-expressing hiPSC-CMs from the two sons. Mechanistic insight from Ca2+ handling expression studies prompted pharmacological rescue experiments, wherein dual dantroline/ranolazine treatment was most effective. Our data are consistent with E99K mutant protein being a central cause of HCM but the three-way interaction between the primary genetic lesion, background (epi)genetics, and donor patient age may influence the pathogenic phenotype. This illustrates the value of isogenic hiPSC-CMs in genotype-phenotype correlations.
AU  - Smith,JGW
AU  - Owen,T
AU  - Bhagwan,JR
AU  - Mosqueira,D
AU  - Scott,E
AU  - Mannhardt,I
AU  - Patel,A
AU  - Barriales-Villa,R
AU  - Monserrat,L
AU  - Hansen,A
AU  - Eschenhagen,T
AU  - Harding,SE
AU  - Marston,S
AU  - Denning,C
DO  - 10.1016/j.stemcr.2018.10.006
EP  - 1243
PY  - 2018///
SN  - 2213-6711
SP  - 1226
TI  - Isogenic pairs of hiPSC-CMs with hypertrophic cardiomyopathy/LVNC-associated ACTC1 E99K mutation unveil differential functional deficits
T2  - Stem Cell Reports
UR  - http://dx.doi.org/10.1016/j.stemcr.2018.10.006
UR  - http://hdl.handle.net/10044/1/66183
VL  - 11
ER  -
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