Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD
Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD
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DOI：
10.1038/sj.ejhg.5201904
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发表时间：
2008-01-01
影响因子：
5.2
通讯作者：
Stratakis, Constantine A.
中科院分区：
文献类型：
--
作者：
Pasini, Barbara;McWhinney, Sarah R.;Stratakis, Constantine A.
胃肠道间质瘤（gist）可能是由KIT和血小板衍生生长因子受体α (PDGFRA)基因的种系突变引起的，可以用甲磺酸伊马替尼（STI571）或其他蛋白酪氨酸激酶抑制剂治疗。然而，并不是所有的GIST都有这些遗传缺陷，一些对STI571没有反应，这表明GIST的发病机制可能涉及其他分子机制。在一部分gist患者中，病变与副神经节瘤有关；这种情况是家族性的，并作为常染色体显性性状传播。我们调查了11例“副神经节瘤和胃间质肉瘤”的合并；在8例（来自7个不相关家族）中，gist是由编码亚基B、C或D的基因（分别为SDHB、SDHC和SDHD基因）的种系突变引起的。在这篇报告中，我们介绍了这些突变对这些基因的分子效应和患者的临床信息。我们得出结论，琥珀酸脱氢酶缺乏症可能是导致gist亚组的原因，这为可能对STI571及其类似物无反应的gist提供了治疗靶点。
Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs.