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

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.

Next-generation sequencing identifies rare variants associated with Noonan syndrome

“…Some (e.g., NS, CS) RASopathies are associated with increased cancer predisposition, but the associated malignancies are distinct. The shared syndromic features of the RASopathies probably reflect ERK hyperactivation, although for NS-ML, at least some phenotypes result from excessive AKT-mTOR activity (4,5). Inter-and intrasyndromic differences are probably due to the distinct effects of specific mutations, modifier alleles, and/or complexities in feedback regulatory pathways in various cell types.…”

Target of rapamcyin (TOR)-based therapeutics for cardiomyopathy

“…Recently, a cardioprotective function of rapamycin has been shown to reverse cardiomyopathy. [1][2][3] However, genetic manipulations of TOR in rodents have not yet supported a therapeutic function of TOR signaling inhibition. 4 In contrast, a detrimental effect on cardiac function was actually suggested in a conditional knockout study of TOR in mouse.…”

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

“…RAS‐MAPK hyperactivation is implicated in JMML/MPD in NS 3. In contrast, HCM in LEOPARD syndrome (LS) is associated with loss‐of‐function mutations in PTPN11 , which result in enhanced PI3K‐AKT and reduced RAS‐MAPK pathway activities 36. Our patient demonstrated the rare manifestation of concurrent JMML and HCM.…”