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}
}
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 -