Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome–associated PTPN11 mutation

LEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-conta...

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Published inThe Journal of clinical investigation Vol. 121; no. 3; pp. 1026 - 1043
Main Authors Marin, Talita M., Keith, Kimberly, Davies, Benjamin, Conner, David A., Guha, Prajna, Kalaitzidis, Demetrios, Wu, Xue, Lauriol, Jessica, Wang, Bo, Bauer, Michael, Bronson, Roderick, Franchini, Kleber G., Neel, Benjamin G., Kontaridis, Maria I.
Format Journal Article
LanguageEnglish
Published United States American Society for Clinical Investigation 01.03.2011
Subjects
Animals
Biomedical research
Cardiomyopathy
Cardiomyopathy, Hypertrophic
Cardiomyopathy, Hypertrophic - drug therapy
Cardiomyopathy, Hypertrophic - genetics
Catalysis
Complications and side effects
Congenital diseases
Disease
Drug therapy
Echocardiography
Female
Gene mutations
Genes
Genetic aspects
Genetic engineering
Health aspects
Heart
Humans
Immunosuppressive Agents - pharmacology
Insects
Kinases
LEOPARD syndrome
LEOPARD Syndrome - drug therapy
LEOPARD Syndrome - genetics
Male
Mice
Mutation
Pathogenesis
Phenotype
Phosphatase
Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics
Proteins
Rapamycin
Risk factors
Signal Transduction
Sirolimus - pharmacology
TOR Serine-Threonine Kinases - metabolism
Canada
Online AccessGet full text
ISSN0021-9738
1558-8238
1558-8238
DOI10.1172/JCI44972

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Abstract LEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11(Y279C/+) (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.
AbstractList LEOPARD syndrome (LS) is an autosomal dominant “RASopathy” that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 ( PTPN11 ) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11Y279C / + ( LS /+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS /+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS /+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS /+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.
LEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11(Y279C/+) (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.LEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11(Y279C/+) (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.
LEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11(Y279C/+) (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.
LEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. [Ptpn11.sup.Y279C/+] ([LS/.sup.+]) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from [LS/.sup.+] mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. [LS/.sup.+] mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in [LS/.sup.+] mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.
Audience Academic
Author Conner, David A.
Lauriol, Jessica
Kalaitzidis, Demetrios
Marin, Talita M.
Franchini, Kleber G.
Kontaridis, Maria I.
Neel, Benjamin G.
Keith, Kimberly
Wang, Bo
Davies, Benjamin
Bronson, Roderick
Wu, Xue
Guha, Prajna
Bauer, Michael
AuthorAffiliation 1 Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2 Department of Internal Medicine, School of Medicine, State University of Campinas, Campinas, Brazil. 3 Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. 4 Department of Hematology/Oncology, Children’s Hospital, Boston, Massachusetts, USA. 5 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. 6 Campbell Family Cancer Research Institute, Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada. 7 Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA. 8 Department of Pathology and 9 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA
AuthorAffiliation_xml – name: 1 Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. 2 Department of Internal Medicine, School of Medicine, State University of Campinas, Campinas, Brazil. 3 Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA. 4 Department of Hematology/Oncology, Children’s Hospital, Boston, Massachusetts, USA. 5 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. 6 Campbell Family Cancer Research Institute, Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada. 7 Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA. 8 Department of Pathology and 9 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/21339643$$D View this record in MEDLINE/PubMed
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Snippet LEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically...
LEOPARD syndrome (LS) is an autosomal dominant “RASopathy” that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically...
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Enrichment Source
StartPage 1026
SubjectTerms Animals
Biomedical research
Cardiomyopathy
Cardiomyopathy, Hypertrophic
Cardiomyopathy, Hypertrophic - drug therapy
Cardiomyopathy, Hypertrophic - genetics
Catalysis
Complications and side effects
Congenital diseases
Disease
Drug therapy
Echocardiography
Female
Gene mutations
Genes
Genetic aspects
Genetic engineering
Health aspects
Heart
Humans
Immunosuppressive Agents - pharmacology
Insects
Kinases
LEOPARD syndrome
LEOPARD Syndrome - drug therapy
LEOPARD Syndrome - genetics
Male
Mice
Mutation
Pathogenesis
Phenotype
Phosphatase
Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics
Proteins
Rapamycin
Risk factors
Signal Transduction
Sirolimus - pharmacology
TOR Serine-Threonine Kinases - metabolism
Title Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome–associated PTPN11 mutation
URI https://www.ncbi.nlm.nih.gov/pubmed/21339643
https://www.proquest.com/docview/856368076
https://www.proquest.com/docview/855206308
https://pubmed.ncbi.nlm.nih.gov/PMC3049377
Volume 121
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