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. OBJECTIVES: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 of JPH2. Pseudo-knock-in (PKI) mice containing
a novel JPH2 variant were subjected to echocardiography, cardiac MRI, hemodynamic
analysis, and histology. RESULTS:A novel JPH2 mutation, 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.
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https://hdl.handle.net/10161/20304Published Version (Please cite this version)
10.1016/j.jacbts.2016.11.004Publication Info
Quick, AP; Landstrom, AP; Wang, Q; Beavers, DL; Reynolds, JO; Barreto-Torres, G; ...
Wehrens, XHT (2017). Novel junctophilin-2 mutation A405S is associated with basal septal hypertrophy and
diastolic dysfunction. JACC. Basic to translational science, 2(1). pp. 56-67. 10.1016/j.jacbts.2016.11.004. Retrieved from https://hdl.handle.net/10161/20304.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Andrew Paul Landstrom
Associate Professor of Pediatrics
Dr. Landstrom is a physician scientist who specializes in the care of children and
young adults with arrhythmias, heritable cardiovascular diseases, and sudden unexplained
death syndromes. As a clinician, he is trained in pediatric cardiology with a focus
on arrhythmias and genetic diseases of the heart. He specializes in caring for patients
with heritable arrhythmia (channelopathies) such as long QT syndrome, Brugada syndrome,
catecholaminergic polymorphic ventricular tachycardia,

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