title: Novel junctophilin-2 mutation A405S is associated with basal septal hypertrophy and diastolic dysfunction.
abstract: BACKGROUND
  Hypertrophic cardiomyopathy (HCM), defined as asymmetric left ventricular hypertrophy, is a leading cause of cardiac death in the young. Perturbations in calcium (Ca2+) handling proteins have been implicated in the pathogenesis of HCM.JPH2-encoded junctophilin 2 is a major component of the junctional membrane complex, the subcellular microdomain involved in excitation-contraction coupling. We hypothesized that a novel JPH2 mutation identified in patients with HCM is causally linked to HCM, and alters intracellular Ca2+signaling in a pro-hypertrophic manner.
  
  
  OBJECTIVE
  To determine using a transgenic mouse model whether a JPH2 mutation found in a HCM patient is responsible for disease development.
  
  
  METHODS
  Genetic interrogation of a large cohort of HCM cases was conducted for all coding exons ofJPH2. Pseudo-knock-in (PKI) mice containing a novelJPH2variant were subjected to echocardiography, cardiac MRI, hemodynamic analysis, and histology.
  
  
  RESULTS
  A novelJPH2mutation, A405S, was identified in a genotype-negative proband with significant basal septal hypertrophy. Although initially underappreciated by traditional echocardiographic imaging, PKI mice with this JPH2 mutation (residue A399S in mice) were found to exhibit similar basal hypertrophy using a newly developed echo imaging plane, and this was confirmed using cardiac MRI. Histological analysis demonstrated cardiomyocyte hypertrophy and disarray consistent with HCM.
  
  
  CONCLUSIONS
  Variant A405S is a novel HCM-associated mutation in JPH2 found in a proband negative for mutations in the canonical HCM-associated genes. Studies in the analogous mouse model demonstrated for the first time a causal link between a JPH2 defect and HCM. Moreover, novel imaging approaches identified subvalvular septal hypertrophy, specific findings also reported in the human JPH2 mutation carrier.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Ann P
authors.initials: AP
authors.lastname: Quick
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, TX, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Landstrom
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Beavers
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Julia O
authors.initials: JO
authors.lastname: Reynolds
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Giselle
authors.initials: G
authors.lastname: Barreto-Torres
authors.affiliation: Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX, USA.
authors.forename: Viet
authors.initials: V
authors.lastname: Tran
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Showell
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Leonne E
authors.initials: LE
authors.lastname: Philippen
authors.affiliation: Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, TX, USA.
authors.forename: Shaine A
authors.initials: SA
authors.lastname: Morris
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Darlene
authors.initials: D
authors.lastname: Skapura
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Bos
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Steen E
authors.initials: SE
authors.lastname: Pedersen
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Robia G
authors.initials: RG
authors.lastname: Pautler
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX, USA.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
keywords: Calcium; hypertrophic cardiomyopathy; junctophilin-2; magnetic resonance imaging