154 Chapter 7 First author and year of publication Species Type of study Main findings Young (2015)45 n/a Review Reviewed PLN mutants Arg9 and Arg14 and how the synergistic changes in SR calcium homeostasis led to impaired cardiac contractility and DCM. Karakikes (2015)46 hiPSC-CMs in vitro, Pathological examination, Genetic restoration Gene correction using TALENs in hiPSC-CMs ameliorate PLN-R14del associated phenotype in vitro. Knock-down of mutant R14del or overexpression of WT PLN also reversed disease phenotype. López-Ayala (2015)47 Human Clinical examination, Genetic analysis A Spanish family was reported exhibiting a disease penetration of 75%. ECG abnormalities are often found in carriers, with low-voltage/attenuated R amplitudes. Fish (2016)48 Human Genetic analysis No PLN-R14del mutation was found in 315 African patients with ACM (n = 111), DCM (n = 95), HCM (n = 40) or PC (n = 69). One PLN c.25C > T (p.R9C) mutation was detected (mutation prevalence = 0.2%). Milano (2016)49 Human Clinical examination, Genetic analysis Rare genetic variants, including PLN-R14del, contribute to the risk of sudden cardiac death. Te Rijdt (2016)50 Human Clinical examination, Pathological examination PLN-R14del cardiomyopathy is characterized by large perinuclear PLN aggregates, which form aggresomes and are degraded via autophagy. Stillitano (2016)51 hiPSC-CMs in vitro, Pathological examination, functional readout, Genetic restoration Three-dimensional EHT shows impaired cardiac contractility due to PLN-R14del. Genomic editing using TALENs restores contractile function. Opbergen (2017)52 n/a Review Review outlines the intracellular cardiac calcium dynamics and relates pathophysiological signaling. Sepehrkhouy (2017)53 Human Pathological examination PLN-associated cardiomyopathies exhibit a distinct fibrosis pattern from other hereditary cardiomyopathies. Fibrosis is most prominently present in the LPW. Te Rijdt (2017)54 Human Pathological examination, Genetic analysis Using immunohistochemical staining of PLN protein aggregates, PLN-R14del cardiomyopathy can be diagnosed sensitively and specifically. Nannenberg (2018)55 Human Clinical Examination Study evaluated ascertainment bias on survival. In PLN-R14del-positive patients, the median age of survival increased from 63.5% (2010) to 65.2 years (2012). Wu (2018)56 Pig ex vivo, model characterization Generation of PLNR14del pigs via CRISPR/ Cpf1‑mediated gene editing and somatic cell nuclear transfer. Heart H&E staining results of 3 months old PLNR14del piglets showed no signifcant differences in tissue morphology or cell shape and size. Hof (2019)57 n/a Review Reviewed studies till 2017. The most striking characteristic is the low-voltage ECGs. Therefore, cardiac and genetic screening is strongly recommended. Te Rijdt (2019)58 Human Clinical examination, Pathological examination, Genetic analysis PLN-R14del phenotype is biventricular, is characterized by fibrofatty replacement and fibrosis, and exhibits a distinct molecular signature compared to ACM. Cheung (2019)59 Human Clinical examination Genetic analysis A Canadian cohort of PLN-R14del patients exhibited similar disease phenotypes as Dutch patients, including VA and ECG abnormalities.
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