Costello and cardio-facio-cutaneous syndromes: Moving toward clinical trials in RASopathies.
Costello and cardio-facio-cutaneous syndromes: Moving toward clinical trials in RASopathies.
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DOI：
10.1002/ajmg.c.30294
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发表时间：
2011-05-15
影响因子：
3.1
通讯作者：
Viskochil, David H.
中科院分区：
文献类型：
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作者：
Rauen, Katherine A.;Banerjee, Anuradha;Bishop, W. Robert;Lauchle, Jennifer O.;McCormick, Frank;McMahon, Martin;Melese, Teri;Munster, Pamela N.;Nadaf, Sorena;Packer, Roger J.;Sebolt-Leopold, Judith;Viskochil, David H.
关键词：
RASo 病是已知的最大的多种先天性异常综合征之一，是由编码 Ras/丝裂原激活蛋白激酶 (MAPK) 通路成分的各种基因的种系突变引起的。 RASopathies 有许多重叠的特征，包括颅面表现、心脏畸形、皮肤、肌肉骨骼、胃肠道和眼部异常、神经认知障碍、肌张力低下以及患癌症的风险增加。 Costello 综合征 (CS) 和心面皮肤 (CFC) 综合征是两种较为罕见的 RASo 病。 CS 是由 HRAS 激活突变引起的，CFC 是由于 BRAF、MEK1 或 MEK2 突变导致 Ras/MAPK 通路中信号传导失调引起的。 Ras/MAPK 通路已在癌症中得到充分研究，是利用特异性抑制该通路的小分子疗法治疗各种恶性肿瘤的有吸引力的抑制靶标。随着许多 Ras/MAPK 通路抑制剂进入临床试验，使用这些分子改善 CS 和 CFC 发育缺陷的想法正在考虑之中。 CS 和 CFC 与同类中的其他综合征一样，具有进行性表型，并且可能适合信号传导的抑制或正常化。
The RASopathies, one of the largest groups of multiple congenital anomaly syndromes known, are caused by germline mutations in various genes encoding components of the Ras/mitogen-activated protein kinase (MAPK) pathway. The RASopathies have many overlapping characteristics, including craniofacial manifestations, cardiac malformations, cutaneous, musculoskeletal, gastrointestinal, and ocular abnormalities, neurocognitive impairment, hypotonia, and an increased risk of developing cancer. Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome are two of the more rare RASopathies. CS is caused by activating mutations in HRAS, and CFC is caused by dysregulation of signaling in the Ras/MAPK pathway due to mutations in BRAF, MEK1, or MEK2. The Ras/MAPK pathway, which has been well-studied in cancer, is an attractive target for inhibition in the treatment of various malignancies utilizing small molecule therapeutics that specifically inhibit the pathway. With many inhibitors of the Ras/MAPK pathway in clinical trials, the notion of using these molecules to ameliorate developmental defects in CS and CFC is under consideration. CS and CFC, like other syndromes in their class, have a progressive phenotype and may be amenable to inhibition or normalization of signaling.
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