Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation
Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation
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DOI：
10.1172/jci44972
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发表时间：
2011-03-01
影响因子：
15.9
通讯作者：
Kontaridis, Maria I.
中科院分区：
文献类型：
--
作者：
Marin, Talita M.;Keith, Kimberly;Kontaridis, Maria I.
LEOPARD综合征（LS）是一种常染色体显性遗传的“RAS病”，表现为先天性心脏病。几乎所有LS病例都是由蛋白质酪氨酸磷酸酶（PTP）、非受体11型（PTPN 11）基因的催化失活突变引起的，该基因编码含有SH 2结构域的PTP-2（SHP 2）。RASopathies通常影响RAS/MAPK通路的组分，但仍不清楚PTPN 11突变如何改变细胞信号传导以产生LS表型。因此，我们产生了携带Ptpn 11突变Y279 C（最常见的LS等位基因之一）的敲入小鼠。Ptpn 11（Y279 C/+）（LS/+）小鼠重现了人类疾病，具有身材矮小、颅面畸形以及肥厚型心肌病（HCM）的形态学、组织学、超声心动图和分子证据。LS/+小鼠的心脏和/或心肌细胞裂解物显示Shp 2与Irs 1的结合增强，Shp 2催化活性降低，并消除激动剂诱发的Erk/Mapk信号传导。LS/+小鼠还表现出基础和激动剂诱导的Akt和mTor活性增加。LS/+小鼠中的心脏缺陷通过用雷帕霉素（mTOR的抑制剂）治疗而完全逆转。我们的研究结果表明，LS突变在体内具有显性负效应，确定增强的mTOR活性是导致LS相关HCM的关键，并建议考虑使用TOR抑制剂治疗LS患者的HCM。
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.