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Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.

Publication ,  Journal Article
Landstrom, AP; Weisleder, N; Batalden, KB; Bos, JM; Tester, DJ; Ommen, SR; Wehrens, XHT; Claycomb, WC; Ko, J-K; Hwang, M; Pan, Z; Ma, J; Ackerman, MJ
Published in: J Mol Cell Cardiol
June 2007

Junctophilin-2 (JPH2) is a cardiac specific member of the junctophilins, a newly characterized family of junctional membrane complex proteins important in physically approximating the plasmalemmal L-type calcium channel and the sarcoplasmic reticulum ryanodine receptor for calcium-induced calcium release. JPH2 knockout mice showed disrupted calcium transients, altered junctional membrane complex formation, cardiomyopathy, and embryonic lethality. Furthermore, JPH2 gene expression is down-regulated in murine cardiomyopathy models. To this end, we explored JPH2 as a novel candidate gene for the pathogenesis of hypertrophic cardiomyopathy (HCM) in humans. Using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of JPH2 was performed on DNA obtained from 388 unrelated patients with HCM. HCM-associated JPH2 mutations were engineered and functionally characterized using immunocytochemistry, cell morphometry measurements, and live cell confocal calcium imaging. Three novel HCM-susceptibility mutations: S101R, Y141H and S165F, which localize to key functional domains, were discovered in 3/388 unrelated patients with HCM and were absent in 1000 ethnic-matched reference alleles. Functionally, each human mutation caused (i) protein reorganization of junctophilin-2, (ii) perturbations in intracellular calcium signaling, and (iii) marked cardiomyocyte hyperplasia. The molecular and functional evidence implicates defective junctophilin-2 and disrupted calcium signaling as a novel pathogenic mechanism for HCM and establishes HCM as the first human disease associated with genetic defects in JPH2. Whether susceptibility for other cardiomyopathies, such as dilated cardiomyopathy, can be conferred by mutations in JPH2 warrants investigation.

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Published In

J Mol Cell Cardiol

DOI

ISSN

0022-2828

Publication Date

June 2007

Volume

42

Issue

6

Start / End Page

1026 / 1035

Location

England

Related Subject Headings

  • Mutation
  • Muscle Proteins
  • Membrane Proteins
  • Immunohistochemistry
  • Humans
  • Case-Control Studies
  • Cardiovascular System & Hematology
  • Cardiomyopathy, Hypertrophic
  • Calcium Signaling
  • 3208 Medical physiology
 

Citation

APA
Chicago
ICMJE
MLA
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Landstrom, A. P., Weisleder, N., Batalden, K. B., Bos, J. M., Tester, D. J., Ommen, S. R., … Ackerman, M. J. (2007). Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. J Mol Cell Cardiol, 42(6), 1026–1035. https://doi.org/10.1016/j.yjmcc.2007.04.006
Landstrom, Andrew P., Noah Weisleder, Karin B. Batalden, J Martijn Bos, David J. Tester, Steve R. Ommen, Xander H. T. Wehrens, et al. “Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.J Mol Cell Cardiol 42, no. 6 (June 2007): 1026–35. https://doi.org/10.1016/j.yjmcc.2007.04.006.
Landstrom AP, Weisleder N, Batalden KB, Bos JM, Tester DJ, Ommen SR, et al. Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. J Mol Cell Cardiol. 2007 Jun;42(6):1026–35.
Landstrom, Andrew P., et al. “Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.J Mol Cell Cardiol, vol. 42, no. 6, June 2007, pp. 1026–35. Pubmed, doi:10.1016/j.yjmcc.2007.04.006.
Landstrom AP, Weisleder N, Batalden KB, Bos JM, Tester DJ, Ommen SR, Wehrens XHT, Claycomb WC, Ko J-K, Hwang M, Pan Z, Ma J, Ackerman MJ. Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. J Mol Cell Cardiol. 2007 Jun;42(6):1026–1035.
Journal cover image

Published In

J Mol Cell Cardiol

DOI

ISSN

0022-2828

Publication Date

June 2007

Volume

42

Issue

6

Start / End Page

1026 / 1035

Location

England

Related Subject Headings

  • Mutation
  • Muscle Proteins
  • Membrane Proteins
  • Immunohistochemistry
  • Humans
  • Case-Control Studies
  • Cardiovascular System & Hematology
  • Cardiomyopathy, Hypertrophic
  • Calcium Signaling
  • 3208 Medical physiology