Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility
Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility
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DOI：
10.1046/j.1365-2265.2003.01914.x
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发表时间：
2003-12-01
影响因子：
3.2
通讯作者：
Maher, ER
中科院分区：
文献类型：
--
作者：
Astuti, D;Hart-Holden, N;Maher, ER
背景 线粒体复合物 II 的三个亚基（SDHB、SDHC 和 SDHD）的种系突变可能与嗜铬细胞瘤 (PC) 和/或头颈副神经节瘤 (HNPGL) 的易感性相关。 方法 为了进一步明确 SDH 亚基突变在这些疾病中的作用，我们分析了一系列 22 名患有 PC 的先证者和遗传证据。 种系 SDHB、SDHC 和 SDHD 突变的易感性（7 例仅患有家族性 PC，1 例患有家族性 PC 和 HNPGL，10 例散发性病例患有多种 PC，4 例为孤立性儿童发病 PC）。此外，我们还分析了 34 例 HNPGL 病例（30 例单发肿瘤孤立病例、3 例多发肿瘤孤立病例和 1 例多发肿瘤家族病例）的 SDHB、SDHC 和 SDHD 体细胞和种系突变。结果 我们在 22 名 PC 先证者中发现了 4 种种系突变（3 种 SDHB 和 1 种 SDHD，3 种新突变）。将这些结果与我们之前的系列相结合，我们在 2/12 (17%) 的仅家族性 PC 亲属、4/5 (80%) 的家族性 PC 和 HNPGL 病例、1/10 的散发性多发性 PC 病例和 2/4 (50%) 的儿科 PC 中检测到种系 SDHB 或 SDHD 突变。 HNPGL 肿瘤中未检测到体细胞突变，但 4 例多发性 HNPGL 病例具有常见的 P81L 种系 SDHD 突变。有趣的是，SDHD 中的沉默 SNP (c.204C > T) 在 HNPGL 病例 (6/34) 中比在对照组 (1/100，P= 0.0011) 中更为常见。将我们的结果与另外两项对 SDHB 和 SDHD 进行分析的大型研究的结果相结合，SDHB 突变最常与嗜铬细胞瘤易感性相关，而 SDHD 与 HNPGL 的发展相关（P = 0.025）。然而，种系 SDHB 和 SDHD 突变表现出相当大的表型变异性，并且基因型-表型相关性很复杂。 结论 与家族性 PC 和 HNPGL 病例相比，仅家族性 PC 病例中种系 SDH 亚基突变的频率显着降低 (P = 0.028)，这表明进一步的 PC 易感基因仍有待鉴定。
BACKGROUND Germline mutations in three subunits of mitochondrial complex II (SDHB, SDHC and SDHD) may be associated with susceptibility to phaeochromocytoma (PC) and/or head and neck paraganglioma (HNPGL).METHODS To further define the role of SDH subunit mutations in these disorders, we analysed a series of 22 probands with PC and evidence of genetic susceptibility (seven with familial PC only, one with familial PC and HNPGL, 10 sporadic cases with multiple PC and four cases of isolated paediatric onset PC) for germline SDHB, SDHC and SDHD mutations. In addition, we analysed 34 cases of HNPGL (30 isolated cases with single tumours, three isolated cases with multiple tumours and one familial case with multiple tumours) for somatic and germline mutations in SDHB, SDHC and SDHD.RESULTS We identified four germline mutations (three SDHB and one SDHD, three novel) in the 22 PC probands. Combining these results with our previous series, we have detected germline SDHB or SDHD mutations in 2/12 (17%) of familial PC only kindreds, 4/5 (80%) of familial PC and HNPGL cases, 1/10 of sporadic multiple PC cases and 2/4 (50%) of paediatric PCs. No somatic mutations were detected in the HNPGL tumours, but four cases with multiple HNPGL had the common P81L germline SDHD mutation. Intriguingly a silent SNP (c.204C > T) in SDHD was significantly more common in HNPGL cases (6/34) than in controls (1/100, P= 0.0011). Combining our results with those from two other large studies in which both SDHB and SDHD have been analysed, SDHB mutations were most commonly associated with phaeochromocytoma susceptibility and SDHD with the development of HNPGL (P = 0.025). However, germline SDHB and SDHD mutations demonstrate considerable phenotypic variability and genotype-phenotype correlations are complex.CONCLUSION The significantly lower frequency (P = 0.028) of germline SDH subunit mutations in familial PC only cases compared to those with familial PC and HNPGL suggests that further PC susceptibility gene(s) remain to be identified.