SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma
SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma
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DOI：
10.1016/s1470-2045(10)70007-3
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发表时间：
2010-04-01
期刊：
影响因子：
51.1
通讯作者：
Robledo, Mercedes
中科院分区：
文献类型：
--
作者：
Bayley, Jean-Pierre;Kunst, Henricus P. M.;Robledo, Mercedes
背景副神经节瘤和嗜铬细胞瘤是一种神经内分泌肿瘤，常与SDHD、SDHC和SDHB的胚系突变相关。以前的研究表明，印记的SDHAF2基因在一个患有副神经节瘤的荷兰大家族中发生了突变。我们的目标是确定SDHAF2突变携带者，评估SDHAF2的临床遗传学意义，并描述相关的临床表型。方法我们在西班牙和荷兰进行了一项多中心研究，研究对象为443例明显散发性的副神经节瘤和嗜铬细胞瘤患者，这些患者没有SDHD、SDHC或SDHB突变。我们分析了315例患者的DNA中SDHAF2的胚系突变；研究了一个子集(n=200)的粗略基因缺失。研究人员对128个肿瘤的DNA进行了体细胞突变研究。我们还检查了一个发病年龄较小的西班牙家系的头颈部副神经节瘤是否存在SDHAF2突变，对该家系进行了单倍型分析，并评估了他们的临床表型。结果我们没有发现任何SDHAF2的种系或体细胞突变，在所分析的明显散发性患者中也没有发现粗大的基因缺失。对西班牙家系的调查发现了一个SDHAF2的致病胚系DNA突变，232G->；A(Gly78Arg)，与荷兰人相同。解释SDHAF2突变在嗜铬细胞瘤中不起重要作用，在头颈部副神经节瘤中罕见。对带有Gly78Arg突变的第二个家族的鉴定表明，这是SDHAF2功能的关键残基。我们的结论是，SDHAF2突变分析在没有SDHD、SDHC或SDHB突变的非常年轻的头颈部副神经节瘤患者中是合理的，并且在所有其他危险基因突变阴性的有家族前科的个体中是合理的。
Background Paragangliomas and phaeochromocytomas are neuroendocrine tumours associated frequently with germline mutations of SDHD, SDHC, and SDHB. Previous studies have shown the imprinted SDHAF2 gene to be mutated in a large Dutch kindred with paragangliomas. We aimed to identify SDHAF2 mutation carriers, assess the clinical genetic significance of SDHAF2, and describe the associated clinical phenotype.Methods We undertook a multicentre study in Spain and the Netherlands in 443 apparently sporadic patients with paragangliomas and phaeochromocytomas who did not have mutations in SDHD, SDHC, or SDHB. We analysed DNA of 315 patients for germline mutations of SDHAF2; a subset (n=200) was investigated for gross gene deletions. DNA from a group of 128 tumours was studied for somatic mutations. We also examined a Spanish family with head and neck paragangliomas with a young age of onset for the presence of SDHAF2 mutations, undertook haplotype analysis in this kindred, and assessed their clinical phenotype.Findings We did not identify any germline or somatic mutations of SDHAF2, and no gross gene deletions were noted in the subset of apparently sporadic patients analysed. Investigation of the Spanish family identified a pathogenic germline DNA mutation of SDHAF2, 232G -> A (Gly78Arg), identical to the Dutch kindred.Interpretation SDHAF2 mutations do not have an important role in phaeochromocytoma and are rare in head and neck paraganglioma. Identification of a second family with the Gly78Arg mutation suggests that this is a crucial residue for the function of SDHAF2. We conclude that SDHAF2 mutation analysis is justified in very young patients with isolated head and neck paraganglioma without mutations in SDHD, SDHC, or SDHB, and in individuals with familial antecedents who are negative for mutations in all other risk genes.