Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway
Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway
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DOI：
10.1017/s1462399408000902
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发表时间：
2008-12-09
影响因子：
6.2
通讯作者：
Rauen, Katherine A.
中科院分区：
文献类型：
--
作者：
Tidyman, William E.;Rauen, Katherine A.
已经出现了一类由Ras诱导的丝裂原活化蛋白激酶（MAPK）级联（Ras-MAPK途径）的失调引起的发育障碍。其中三种疾病-努南综合征、科斯特洛综合征和心-面-皮肤综合征-具有重叠的表型特征，其特征在于独特的面部畸形、心脏缺陷、肌肉骨骼和皮肤异常以及神经认知延迟。与这些疾病相关的种系突变是在编码Ras-MAPK途径蛋白质的基因中。体外研究已经确定，这些突变中的绝大多数导致信号转导途径增加，但通常程度低于与癌症相关的相同基因中的体细胞突变。Ras-MAPK通路在细胞周期、分化、生长和衰老的调节中是必不可少的，因此影响其功能的种系突变对发育产生深远影响也就不足为奇了。在这里，我们回顾了已知的努南综合征，Costello综合征和心面皮肤综合征相关的分子病变的临床后果，并探讨可能的治疗方法。
A class of developmental disorders caused by dysregulation of the Ras-induced mitogen-activated protein kinase (MAPK) cascade (the Ras-MAPK pathway) has emerged. Three of these disorders - Noonan, Costello and cardio-facio-cutaneous syndromes - have overlapping phenotypic features characterised by distinctive facial dysmorphia, cardiac defects, musculoskeletal and cutaneous abnormalities, and neurocognitive delay. The germline mutations associated with these disorders are in genes that encode proteins of the Ras-MAPK pathway. In vitro studies have determined that the overwhelming majority of these mutations result in increased signal transduction down the pathway, but usually to a lesser degree than somatic mutations in the same genes that are associated with cancer. The Ras-MAPK pathway is essential in the regulation of the cell cycle, differentiation, growth and senescence, so it is not surprising that germline mutations that affect its function have profound effects on development. Here we review the clinical consequences of the known molecular lesions associated with Noonan syndrome, Costello syndrome and cardio-facio-cutaneous syndrome, and explore possible therapeutic modalities for treatment.