Novel junctophilin-2 mutation A405S is associated with basal septal hypertrophy and diastolic dysfunction.

dc.contributor.author

Quick, AP

dc.contributor.author

Landstrom, AP

dc.contributor.author

Wang, Q

dc.contributor.author

Beavers, DL

dc.contributor.author

Reynolds, JO

dc.contributor.author

Barreto-Torres, G

dc.contributor.author

Tran, V

dc.contributor.author

Showell, J

dc.contributor.author

Philippen, LE

dc.contributor.author

Morris, SA

dc.contributor.author

Skapura, D

dc.contributor.author

Bos, JM

dc.contributor.author

Pedersen, SE

dc.contributor.author

Pautler, RG

dc.contributor.author

Ackerman, MJ

dc.contributor.author

Wehrens, XHT

dc.date.accessioned

2020-04-01T13:30:45Z

dc.date.available

2020-04-01T13:30:45Z

dc.date.issued

2017-02

dc.date.updated

2020-04-01T13:30:43Z

dc.description.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.

dc.identifier

S2452-302X(16)30170-X

dc.identifier.issn

2452-302X

dc.identifier.issn

2452-302X

dc.identifier.uri

https://hdl.handle.net/10161/20304

dc.language

eng

dc.publisher

Elsevier BV

dc.relation.ispartof

JACC. Basic to translational science

dc.relation.isversionof

10.1016/j.jacbts.2016.11.004

dc.subject

Calcium

dc.subject

hypertrophic cardiomyopathy

dc.subject

junctophilin-2

dc.subject

magnetic resonance imaging

dc.title

Novel junctophilin-2 mutation A405S is associated with basal septal hypertrophy and diastolic dysfunction.

dc.type

Journal article

duke.contributor.orcid

Landstrom, AP|0000-0002-1878-9631

pubs.begin-page

56

pubs.end-page

67

pubs.issue

1

pubs.organisational-group

School of Medicine

pubs.organisational-group

Cell Biology

pubs.organisational-group

Pediatrics, Cardiology

pubs.organisational-group

Duke

pubs.organisational-group

Basic Science Departments

pubs.organisational-group

Pediatrics

pubs.organisational-group

Clinical Science Departments

pubs.publication-status

Published

pubs.volume

2

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
Novel junctophilin-2 mutation A405S is associated with basal septal hypertrophy and diastolic dysfunction.pdf
Size:
2.56 MB
Format:
Adobe Portable Document Format
Description:
Published version