Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion improves cardiac function and survival

Jason C Choi, Wei Wu, Elizabeth Phillips, Robin Plevin, Fusako Sera, Shunichi Homma, Howard J. Worman

Research output: Contribution to journal › Article

4 Citations (Scopus)

Abstract

Mutations in the lamin A/C gene (LMNA) encoding the nuclear intermediate filament proteins lamins A and C cause a group of tissue-selective diseases, the most common of which is dilated cardiomyopathy (herein referred to as LMNA cardiomyopathy) with variable skeletal muscle involvement. We previously showed that cardiomyocyte-specific overexpression of dual specificity protein phosphatase 4 (DUSP4) is involved in the pathogenesis of LMNA cardiomyopathy. However, how mutations in LMNA activate Dusp4 expression and whether it is necessary for the development of LMNA cardiomyopathy are currently unknown. We now show that female LmnaH222P/H222P mice, a model for LMNA cardiomyopathy, have increased Dusp4 expression and hyperactivation of extracellular signal-regulated kinase (ERK) 1/2 with delayed kinetics relative to male mice, consistent with the sex-dependent delay in the onset and progression of disease. Mechanistically, we show that the H222P amino acid substitution in lamin A enhances its binding to ERK1/2 and increases sequestration at the nuclear envelope. Finally, we show that genetic deletion of Dusp4 has beneficial effects on heart function and prolongs survival in LmnaH222P/H222P mice. These results further establish Dusp4 as a key contributor to the pathogenesis of LMNA cardiomyopathy and a potential target for drug therapy.
LanguageEnglish
JournalHuman Molecular Genetics
Early online date16 Apr 2018
DOIs
Publication statusE-pub ahead of print - 16 Apr 2018

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Dual-Specificity Phosphatases
Lamin Type A
Cardiomyopathies
Mutation
Genes
Intermediate Filament Proteins
protein phosphatase 4
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Nuclear Envelope
Dilated Cardiomyopathy
Amino Acid Substitution
Nuclear Proteins
Protein C
Cardiac Myocytes
Disease Progression
Skeletal Muscle

Keywords

  • cardiac myociyte
  • cariomyopathy
  • pharmacotherapy
  • cardiac function
  • protein overexpression

Cite this

Choi, Jason C ; Wu, Wei ; Phillips, Elizabeth ; Plevin, Robin ; Sera, Fusako ; Homma, Shunichi ; Worman, Howard J. / Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion improves cardiac function and survival. In: Human Molecular Genetics . 2018.
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abstract = "Mutations in the lamin A/C gene (LMNA) encoding the nuclear intermediate filament proteins lamins A and C cause a group of tissue-selective diseases, the most common of which is dilated cardiomyopathy (herein referred to as LMNA cardiomyopathy) with variable skeletal muscle involvement. We previously showed that cardiomyocyte-specific overexpression of dual specificity protein phosphatase 4 (DUSP4) is involved in the pathogenesis of LMNA cardiomyopathy. However, how mutations in LMNA activate Dusp4 expression and whether it is necessary for the development of LMNA cardiomyopathy are currently unknown. We now show that female LmnaH222P/H222P mice, a model for LMNA cardiomyopathy, have increased Dusp4 expression and hyperactivation of extracellular signal-regulated kinase (ERK) 1/2 with delayed kinetics relative to male mice, consistent with the sex-dependent delay in the onset and progression of disease. Mechanistically, we show that the H222P amino acid substitution in lamin A enhances its binding to ERK1/2 and increases sequestration at the nuclear envelope. Finally, we show that genetic deletion of Dusp4 has beneficial effects on heart function and prolongs survival in LmnaH222P/H222P mice. These results further establish Dusp4 as a key contributor to the pathogenesis of LMNA cardiomyopathy and a potential target for drug therapy.",
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Choi, JC, Wu, W, Phillips, E, Plevin, R, Sera, F, Homma, S & Worman, HJ 2018, 'Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion improves cardiac function and survival' Human Molecular Genetics . https://doi.org/10.1093/hmg/ddy134

Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion improves cardiac function and survival. / Choi, Jason C; Wu, Wei; Phillips, Elizabeth; Plevin, Robin; Sera, Fusako; Homma, Shunichi; Worman, Howard J.

In: Human Molecular Genetics , 16.04.2018.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion improves cardiac function and survival

AU - Choi, Jason C

AU - Wu, Wei

AU - Phillips, Elizabeth

AU - Plevin, Robin

AU - Sera, Fusako

AU - Homma, Shunichi

AU - Worman, Howard J.

PY - 2018/4/16

Y1 - 2018/4/16

N2 - Mutations in the lamin A/C gene (LMNA) encoding the nuclear intermediate filament proteins lamins A and C cause a group of tissue-selective diseases, the most common of which is dilated cardiomyopathy (herein referred to as LMNA cardiomyopathy) with variable skeletal muscle involvement. We previously showed that cardiomyocyte-specific overexpression of dual specificity protein phosphatase 4 (DUSP4) is involved in the pathogenesis of LMNA cardiomyopathy. However, how mutations in LMNA activate Dusp4 expression and whether it is necessary for the development of LMNA cardiomyopathy are currently unknown. We now show that female LmnaH222P/H222P mice, a model for LMNA cardiomyopathy, have increased Dusp4 expression and hyperactivation of extracellular signal-regulated kinase (ERK) 1/2 with delayed kinetics relative to male mice, consistent with the sex-dependent delay in the onset and progression of disease. Mechanistically, we show that the H222P amino acid substitution in lamin A enhances its binding to ERK1/2 and increases sequestration at the nuclear envelope. Finally, we show that genetic deletion of Dusp4 has beneficial effects on heart function and prolongs survival in LmnaH222P/H222P mice. These results further establish Dusp4 as a key contributor to the pathogenesis of LMNA cardiomyopathy and a potential target for drug therapy.

AB - Mutations in the lamin A/C gene (LMNA) encoding the nuclear intermediate filament proteins lamins A and C cause a group of tissue-selective diseases, the most common of which is dilated cardiomyopathy (herein referred to as LMNA cardiomyopathy) with variable skeletal muscle involvement. We previously showed that cardiomyocyte-specific overexpression of dual specificity protein phosphatase 4 (DUSP4) is involved in the pathogenesis of LMNA cardiomyopathy. However, how mutations in LMNA activate Dusp4 expression and whether it is necessary for the development of LMNA cardiomyopathy are currently unknown. We now show that female LmnaH222P/H222P mice, a model for LMNA cardiomyopathy, have increased Dusp4 expression and hyperactivation of extracellular signal-regulated kinase (ERK) 1/2 with delayed kinetics relative to male mice, consistent with the sex-dependent delay in the onset and progression of disease. Mechanistically, we show that the H222P amino acid substitution in lamin A enhances its binding to ERK1/2 and increases sequestration at the nuclear envelope. Finally, we show that genetic deletion of Dusp4 has beneficial effects on heart function and prolongs survival in LmnaH222P/H222P mice. These results further establish Dusp4 as a key contributor to the pathogenesis of LMNA cardiomyopathy and a potential target for drug therapy.

KW - cardiac myociyte

KW - cariomyopathy

KW - pharmacotherapy

KW - cardiac function

KW - protein overexpression

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DO - 10.1093/hmg/ddy134

M3 - Article

JO - Human Molecular Genetics

T2 - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

ER -

Choi JC, Wu W, Phillips E, Plevin R, Sera F, Homma S et al. Elevated dual specificity protein phosphatase 4 in cardiomyopathy caused by lamin A/C gene mutation is primarily ERK1/2-dependent and its depletion improves cardiac function and survival. Human Molecular Genetics . 2018 Apr 16. https://doi.org/10.1093/hmg/ddy134

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