A Novel PRKAG2 Mutation (K475E): Early‐Onset Cardiac Phenotype and Targeted Therapy

Abstract

BackgroundMutations in PRKAG2 have been implicated in hypertrophic cardiomyopathy (HCM). We identified a novel PRKAG2 mutation, K475E, in a neonate with prenatal onset of HCM noted on a 27‐week prenatal ultrasound. We have demonstrated in vitro that K475E mutation led to increases in cardiomyocytes size and area which can be reversed by rapamycin.ObjectiveTo characterize K475E‐induced cardiac phenotype in vivo, we developed two new transgenic mouse lines with cardiac‐specific expression of the human wild type (TgWT) or K475E mutant (TgK475E) PRKAG2. The goal of this study was to explore the effectiveness of rapamycin for targeted therapy for PRKAG2 mutation‐induced HCM.MethodsHuman WT and K475E DNA constructs were inserted into a pBluescript vector with the mouse α‐myosin heavy chain promoter. Transgenic mice were established by pronucleus microinjection. Rapamycin was treated from two‐week to six‐aged mice. Cardiac hypertrophy was examined and cardiac function changes were monitored by echocardiography.ResultsHypertrophy in TgK475E mice was confirmed by their significant increases in heart weight/body weight and heart weight/tibial length ratios versus the non‐transgenic control and TgWT mice. Histology revealed large vacuoles and high glycogen content in TgK475E myocytes throughout the ventricles. Echocardiography confirmed that LV mass dramatically increased in TgK475E mice starting from 5 weeks of age. Rapamycin treatment dramatically decreased 1) the ratios of heart weight/body weight and heart weight/tibia length and 2) glycogen overload in TgK475E mice. Moreover, K475E mutation caused inhibition of AMPK which was rectified by rapamycin treatment.ConclusionThese results indicate the transgenic mouse model reflects the early onset phenotype of the K475E mutation‐induced HCM. The mTOR signaling pathway is involved in K475E induced HCM. Our study suggests that mTOR inhibition strategy as targeted therapy for PRKAG2 induced HCM is effective and should be studied further.Support or Funding Information1. NIH P30GM114750 2. Oh‐Zopfi Research Award, Women & Infant's Hospital, RI.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.