Abstract
BackgroundAnimal studies suggested that blocking the activation of the mammalian target of rapamycin (mTOR) pathway might be effective to treat cardiac hypertrophy in LEOPARD syndrome (LS) caused by PTPN11 mutations.ResultsIn the present study, mTOR pathway activity was examined in human myocardial samples from two patients with LS, four patients with hypertrophic cardiomyopathy (HCM), and four normal controls. The two patients with LS had p.Y279C and p.T468 M mutations of the PTPN11 gene, respectively. Although PTPN11 mutation showed initially positive regulation on phosphoinositide 3-kinase, overall the mTOR complex 1 pathway showed widely attenuated activity in LS. This included mildly hypophosphorylated mTOR and ribosomal protein S6 kinase and significantly hypophosphorylated Akt308 and ribosomal protein S6, which is similar to HCM. Akt473 is a basal molecule of the mTOR complex 2 pathway. Akt473 was less affected and showed hyperactivity in LS compared with HCM and normal controls. Additionally, MAPK/ERK kinase and ERK1/2 were significantly more phosphorylated in both HCM and LS than normal controls.ConclusionsIn LS, the mTOR signaling pathway shows similar activity to HCM and is attenuated compared with normal controls. Thus, caution should be applied when using rapamycin to treat heart hypertrophy in LS.
Highlights
Animal studies suggested that blocking the activation of the mammalian target of rapamycin pathway might be effective to treat cardiac hypertrophy in LEOPARD syndrome (LS) caused by PTPN11 mutations
Loss-of-function mutation of Shp2 protein in LS leads to the pleiotropic manifestations aforementioned
Gain-of-function mutations of PTPN11 lead to a systemic presentation that overlaps quite much with syndrome caused by loss-of-function mutations
Summary
Animal studies suggested that blocking the activation of the mammalian target of rapamycin (mTOR) pathway might be effective to treat cardiac hypertrophy in LEOPARD syndrome (LS) caused by PTPN11 mutations. LEOPARD Syndrome (LS) is a very rare autosomal dominant disease, and named for its major symptoms of Lentigines, Electrocardiography conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness [1, 2]. Since it was first reported by Zeisler and Becker in. At least 9 mutations involving 7 amino acid sites have been reported. These mutations may affect different functions of the Shp protein. Understanding the abnormalities of signaling pathways will be vital in the treatment of LS
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