Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Trends Cardiovasc Med. 2011 May;21(4):97-104. doi: 10.1016/j.tcm.2012.03.006.
In this review, we focus on elucidating the cardiac function of germline mutations in the PTPN11 gene, encoding the Src homology-2 (SH2) domain-containing protein tyrosine phosphatase SHP2. PTPN11 mutations cause LEOPARD syndrome (LS) and Noonan syndrome (NS), two disorders that are part of a newly classified family of autosomal dominant syndromes termed "RASopathies," which are caused by germline mutations in components of the RAS/RAF/MEK/ERK mitogen activating protein kinase pathway. LS and NS mutants have opposing biochemical properties, and yet, in patients, these mutations produce similar cardiac abnormalities. Precisely how LS and NS mutations lead to such similar disease etiology remains largely unknown. Recent complementary in vitro, ex vivo, and in vivo analyses reveal new insights into the functions of SHP2 in normal and pathological cardiac development. These findings also reveal the need for individualized therapeutic approaches in the treatment of patients with LS and NS and, more broadly, patients with the other "RASopathy" gene mutations as well.
在这篇综述中，我们重点阐述了 PTPN11 基因（编码含有 Src 同源结构域-2（SH2）的蛋白酪氨酸磷酸酶 SHP2）种系突变对心脏功能的影响。PTPN11 突变可导致 LEOPARD 综合征（LS）和 Noonan 综合征（NS），这两种疾病是一种新分类的常染色体显性综合征家族的一部分，称为“RAS 病”，其由 RAS/RAF/MEK/ERK 丝裂原激活蛋白激酶途径成分的种系突变引起。LS 和 NS 突变具有相反的生化特性，但在患者中，这些突变会导致相似的心脏异常。LS 和 NS 突变如何导致如此相似的疾病病因在很大程度上仍不清楚。最近的体外、离体和体内分析提供了新的见解，揭示了 SHP2 在正常和病理性心脏发育中的功能。这些发现还表明，需要针对 LS、NS 患者以及更广泛的其他“RAS 病”基因突变患者采用个体化的治疗方法。
