In:
Orphanet Journal of Rare Diseases, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2019-12)
Abstract:
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. Results In 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 Akt 308 and ribosomal protein S6, which is similar to HCM. Akt 473 is a basal molecule of the mTOR complex 2 pathway. Akt 473 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. Conclusions In 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.
Type of Medium:
Online Resource
ISSN:
1750-1172
DOI:
10.1186/s13023-019-1204-4
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2019
detail.hit.zdb_id:
2225857-7
