SDHA is a tumor suppressor gene causing paraganglioma
SDHA is a tumor suppressor gene causing paraganglioma
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DOI：
10.1093/hmg/ddq206
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发表时间：
2010-08-01
影响因子：
3.5
通讯作者：
Gimenez-Roqueplo, Anne-Paule
中科院分区：
文献类型：
--
作者：
Burnichon, Nelly;Briere, Jean-Jacques;Gimenez-Roqueplo, Anne-Paule
线粒体琥珀酸辅酶Q还原酶（复合体II）由SDHA、SDHB、SDHC和SDHD四个亚基组成。SDHB、SDHC、SDHD和SDHAF2[琥珀酸脱氢酶（SDH）复合体组装因子2编码]的杂合种系突变可导致遗传性副神经节瘤和嗜铬细胞瘤。令人惊讶的是，SDHA与副神经节瘤/嗜铬细胞瘤综合征之间没有遗传联系。我们在一名患有儿茶酚胺分泌腹部副神经节瘤的女性中发现了一种杂合的SDHA突变p.a g589trp。通过免疫组化研究SDHA、SDHB、HIF-1 α和CD34蛋白的表达，以及在酵母模型中检测突变的影响，来评估SDHA突变体的功能。微阵列分析研究了参与能量代谢和缺氧途径的基因表达。我们还通过BAC阵列比较基因组杂交研究了202个副神经节瘤或嗜铬细胞瘤在SDHA、SDHB、SDHC和SDHD位点的杂合性缺失（LOH）。体内和体外功能研究表明，SDHA突变导致肿瘤组织和酵母模型中SDH酶活性的丧失。免疫组织化学和转录组分析证实，SDHA突变引起假性缺氧，导致随后血管生成增加，与其他SDHx基因突变一样。在患者肿瘤的SDHA位点检测到LOH，但在大量副神经节瘤和嗜铬细胞瘤中仅存在4.5%。SDHA基因应该被添加到三羧酸循环蛋白的基因列表中，作为肿瘤抑制基因，现在可以被认为是一个新的副神经节瘤/嗜铬细胞瘤易感基因
Mitochondrial succinate-coenzyme Q reductase (complex II) consists of four subunits, SDHA, SDHB, SDHC and SDHD. Heterozygous germline mutations in SDHB, SDHC, SDHD and SDHAF2 [encoding for succinate dehydrogenase (SDH) complex assembly factor 2] cause hereditary paragangliomas and pheochromocytomas. Surprisingly, no genetic link between SDHA and paraganglioma/pheochromocytoma syndrome has ever been established. We identified a heterozygous germline SDHA mutation, p.Arg589Trp, in a woman suffering from catecholamine-secreting abdominal paraganglioma. The functionality of the SDHA mutant was assessed by studying SDHA, SDHB, HIF-1 alpha and CD34 protein expression using immunohistochemistry and by examining the effect of the mutation in a yeast model. Microarray analyses were performed to study gene expression involved in energy metabolism and hypoxic pathways. We also investigated 202 paragangliomas or pheochromocytomas for loss of heterozygosity (LOH) at the SDHA, SDHB, SDHC and SDHD loci by BAC array comparative genomic hybridization. In vivo and in vitro functional studies demonstrated that the SDHA mutation causes a loss of SDH enzymatic activity in tumor tissue and in the yeast model. Immunohistochemistry and transcriptome analyses established that the SDHA mutation causes pseudo-hypoxia, which leads to a subsequent increase in angiogenesis, as other SDHx gene mutations. LOH was detected at the SDHA locus in the patient's tumor but was present in only 4.5% of a large series of paragangliomas and pheochromocytomas. The SDHA gene should be added to the list of genes encoding tricarboxylic acid cycle proteins that act as tumor suppressor genes and can now be considered as a new paraganglioma/pheochromocytoma susceptibility gene