Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma
Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma
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DOI：
10.1086/321282
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发表时间：
2001-07-01
影响因子：
9.8
通讯作者：
Maher, ER
中科院分区：
文献类型：
--
作者：
Astuti, D;Latif, F;Maher, ER
嗜铬细胞瘤是继发性高血压的重要原因。虽然嗜铬细胞瘤的易感性可能与肿瘤抑制基因VHL和NF 1以及原癌基因RET的种系突变有关，但大多数非综合征型家族性嗜铬细胞瘤的遗传基础尚不清楚。最近，嗜铬细胞瘤的易感性已与生殖系SDHD突变。生殖系SDHD突变最初在遗传性副神经节瘤中描述，这是一种显性遗传疾病，其特征在于头部和颈部的血管肿瘤，最常见于颈动脉分叉处。琥珀酸脱氢酶的两种组分SDHC和SDHD的基因产物将形成催化核心的另外两种组分SDHA和SDHB的基因产物锚在线粒体内膜上。虽然SDHC和SDHD突变可能导致遗传性副神经节瘤，但种系SDHA突变与幼年性脑病相关，SDHB突变的表型后果尚未确定。为了探讨嗜铬细胞瘤的遗传原因，我们分析了家族性和散发性病例中的SDHB和SDHC。在5例家族性嗜铬细胞瘤患者中的2例、3例嗜铬细胞瘤和副神经节瘤易感患者中的2例和24例散发性嗜铬细胞瘤患者中的1例中检测到失活SDHB突变。这些发现扩展了线粒体功能障碍和肿瘤发生之间的联系，并表明生殖系SDHB突变是嗜铬细胞瘤易感性的重要原因。
The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.