Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation
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Updated: May 4, 2026
Isolation, Culture, and Functional Characterization of Adult Mouse Cardiomyoctyes
Published on: September 25, 2013
Talita M Marin1, Kimberly Keith, Benjamin Davies
1Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
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.
Insights
LEOPARD syndrome (LS) is linked to PTPN11 gene mutations. This study reveals that enhanced mTOR activity drives LS-associated hypertrophic cardiomyopathy (HCM) in mice, suggesting mTOR inhibitors as a potential treatment.
Area of Science:
- Genetics and Molecular Biology
- Cardiology
- Developmental Biology
Background:
- LEOPARD syndrome (LS) is an autosomal dominant RASopathy characterized by congenital heart disease, often linked to PTPN11 gene mutations.
- PTPN11 encodes SHP2 phosphatase, a key regulator of the RAS/MAPK pathway, but the precise mechanisms by which LS-associated mutations cause disease phenotypes remain unclear.
Purpose of the Study:
- To investigate the in vivo cellular signaling alterations caused by a common LEOPARD syndrome PTPN11 mutation.
- To determine the role of enhanced mTOR signaling in the development of hypertrophic cardiomyopathy (HCM) in LS.
Main Methods:
- Generated knockin mice (Ptpn11(Y279C/+)) modeling a common LS-associated PTPN11 mutation.
- Analyzed cardiac morphology, histology, echocardiography, and molecular signaling pathways (RAS/MAPK, Akt, mTOR) in LS mice.
- Assessed the therapeutic effect of rapamycin (an mTOR inhibitor) on cardiac defects in LS mice.
Main Results:
- LS mice exhibited short stature, craniofacial dysmorphia, and hypertrophic cardiomyopathy (HCM), recapitulating human LS.
- Ptpn11(Y279C/+) mutation led to decreased SHP2 catalytic activity, abrogated Erk/MAPK signaling, and enhanced basal and agonist-induced Akt/mTOR activity.
- Rapamycin treatment completely reversed cardiac defects in LS mice.
Conclusions:
- LS-associated PTPN11 mutations exert dominant-negative effects in vivo.
- Enhanced mTOR signaling is a critical driver of LS-associated HCM.
- mTOR inhibitors represent a potential therapeutic strategy for treating HCM in LEOPARD syndrome patients.
