153 Phospholamban R14del Cardiomyopathy: a systematic summary of the pathophysiological mechanisms 7 derived induced pluripotent stem cell-derived models, one paper described the PLNR14del pig model and one PLNR14del zebrafish model was reported. Table 1: Systematic summary of clinical and research studies in PLN-R14del cardiomyopathy. Studies are sorted based on the year of publication. First author and year of publication Species Type of study Main findings Haghighi (2006)32 Human, Mouse Clinical and pathological examination, Genetic analysis, in vivo, in vitro The PLN-R14del mutation was identified in a Greek family. PLN-R14Del mice recapitulate human cardiomyopathy. Possibly super-inhibition of SERCA2a by mutant monomeric PLN. DeWitt (2006)33 Human Clinical examination, Genetic analysis Screening of a cohort of 260 unrelated DCM patients for mutations in the PLN gene, identified 1 family with PLN-R14del. Posch (2009)34 Human Clinical examination, Genetic analysis PLN-R14del causes abnormal ECG phenotype with low R amplitudes irrespective of echocardiographic abnormalities. Indication for fibrosis as a primary process. Haghighi (2012)35 Mouse Pathological examination, in vivo, ex vivo, in silico PLN-R14del is misrouted to the sarcolemma, in absence of endogenous PLN, alters NKA activity which subsequently leads to cardiac remodeling. Ceholski (2012)36 n/a in silico PLN-R14del has a dominant-negative effect on SERCA2a function. Hydrophobic imbalance in the cytoplasmic domain of PLN might be a predictor of DCM. Van der Zwaag (2012)37 Human Clinical examination, Pathological examination, Genetic analysis PLN mutation carriers diagnosed with DCM show arrhythmogenic phenotype and cardiomyopathy as well, including sudden cardiac death at a young age. Van der Zwaag (2013)38 Human Epidemiological analysis, Genetic analysis Geographic origin of PLN-R14del is likely EastFriesland (The Netherlands), where the R14del variant originated 575-825 years ago. Van der Heijden (2013)39 n/a Review Reviewed PLN studies till 2013. In the near future, the goal should be to identify all carriers of the PLNR14del mutation to be able to prevent SCD. Groeneweg (2013)40 Human Clinical examination, Pathological examination, Genetic analysis Due to the discovery of the ACM phenotype, the number of PLN-R14del patients contributes substantially to the revised TFC of ACM cardiomyopathy. Gho (2014)41 Human Pathological Examination Using a novel histological quantification method, myocardial fibrosis is mainly present in the LPW and adipose tissue in the RV wall. Van Rijsingen (2014)42 Human Clinical examination, Genetic analysis PLN-R14del carriers are at high risk for VA and end-stage heart failure. No association between participation in high dynamic sports and malignant Vas. Bhonsale (2015)43 Human Genetic Analysis Pathogenic mutations were identified in 577 patients (241 families) from USA and Dutch ARVD/C cohorts. 5.7% carried the PLN-R14del mutation. Vostrikov (2015)44 n/a in silico Deletion of R14 weakens membrane interaction in the cytoplasmic domain, causing a loss of function. Phosphorylation does not reverse the inhibitory effect.
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