头颈部副神经节瘤患者琥珀酸脱氢酶基因致病突变研究
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摘要
头颈部副神经节瘤是一种少见肿瘤疾病,好发于颈动脉体、颈静脉窝、鼓室和迷走神经等部位。近年来研究发现,副神经节瘤与琥珀酸脱氢酶(succinate dehydrogenase, SDH)亚单位的编码基因突变相关。为掌握中国人群头颈部副神经节瘤患者中琥珀酸脱氢酶基因的突变特点以及对疾病的影响,本研究搜集家族性和散发头颈部副神经节瘤患者DNA样本和临床资料,运用分子生物学技术和遗传学研究方法,对患者的SDH基因突变进行了相关研究。
本研究共分为四个部分：
第一部分头颈部副神经节瘤患者临床资料和DNA样本的搜集
本部分研究工作查阅自2002年至今在我院经手术治疗后病理证实为副神经节瘤患者病历,设计临床信息登记表,联系患者进行回访,并邀请其参与本研究。在获得知情同意后,详细完善临床资料及家系情况,获取患者血样并提取DNA备用。对近期手术的患者以及研究阶段新入院的患者,在复查随访和术后阶段亦纳入本研究中。同时,从病理科调取所有患者的肿瘤组织石蜡包埋肿瘤组织标本,提取DNA备用。共搜集头颈部副神经节瘤患者血样34例,石蜡包埋组织样本83例(含34例已获取血样的患者)。提取了34例患者的血样DNA(男性9例、女性25例)和30例患者(男性13例、女性17例)的石蜡包埋组织样本DNA。
第二部分琥珀酸脱氢酶基因点突变检测
本部分研究对64例头颈部副神经节瘤患者的DNA样本进行了SDHB、SDHC、SDHD和SDHAF2基因突变检测。根据实验需要设计SDHB、SDHC和SDHD基因各外显子扩增引物(SDHAF2使用文献引物),经PCR扩增后行序列分析。BLAST序列对比找出SDH基因突变,并通过基因突变数据库对比、突变类型分析、突变位点物种保守性分析等方法,判断其致病性。对特殊突变通过PCR扩增子质粒克隆及单克隆测序分析进行进一步验证。
本部分研究发现48.5%(31／64)的患者携带有SDHB (10例)、SDHC (3例)或SDHD(18例)基因突变,3者的检出率分别为16%、5%和28%,未发现有患者携带SDHAF2基因突变。其中发现了9种新突变,部分结果已提交至SDH突变数据并可在线查询。34例获取了静脉血样的患者中,61.7%(21／34)携带有SDH基因突变(SDHB7例,SDHC 3例,SDHD 11例)；30例检测肿瘤石蜡包埋组织样本DNA的患者中,仅33.3%(10／30)发现携带有SDH基因突变(SDHB 4例,SDHD 7例),小于静脉血样组,p＜0.005。
6例家族性患者均携带SDHD基因突变,占携带SDHD突变的患者总数的33%(6／18),6例多发肿瘤患者亦均为SDHD突变携带者,其中3例为家族性发病患者。2例恶性肿瘤患者均携带有SDH突变,SDHB和SDHD各1例。
第三部分琥珀酸脱氢酶基因大片段缺失检测
本研究对PCR扩增直接测序未发现有突变的33例患者运用多重连接依赖式探针扩增技术对SDH基因的各外显子进行了拷贝数异常检测。未发现有患者的SDH基因拷贝数有异常,说明无染色体重排引起的SDH基因区域大片段缺失。
第四部分多发突变的单体型分析和创始者效应分析
对SDHD基因中出现的多发突变,通过构建各家系的微卫星单体型并将各患者的单体型进行比较,发现携带SDHD c.3G>C突变的4例患者中,有3个患者有相同的微卫星等位基因组合。在75例正常人群中统计了各等位基因的频率,判断他们共享的等位基因组合在正常人群中的概率仅2×10-8～5×10-5,4个不相关的家系同时携带此组合的几率则更小,因此考虑该基因突变为创始者效应所致。
总结：研究发现64例头颈部副神经节瘤患者中48.5%携带有SDH基因突变,包括10例SDHB、3例SDHC和18例SDHD基因突变,其中9种为新突变。没有发现患者携带SDHAF2基因突变；多重连接依赖式探针扩增法没有在患者中发现有SDH基因大片段缺失；单体型分析证实了一个中国患者中的多发突变SDHD c.3G>C为创始者突变。
Paragangliomas are rare tumors occurring at head and neck area. Recently, it has been revealed that paragangliomas have a relationship with germline mutations of succinate dehydrogenase encoding genes. To evaluate the role and characteristics of SDH gene mutations in Chinese patients, we collected DNA samples of familiar and sporadic patients with head and neck paraganliomas and screened for germline mutations. We also analyzed the pathogenicity of the mutations and genotyped the haplotypes of the patients with same mutations.
The study consists of 4 portions:
Part 1:Collection of clinical data and DNA samples of HNPGL patients
We recalled the case records on PGL and select the HNPGL cases confirmed by pathologic diagnosis. We contacted the patients and informed them about our study. With their consents, we registered their detailed clinical and familiar information and we collected blood samples from every patient and the formalin-fixed and paraffin-embedded (FFPE) tissue samples from the department of Pathology. In total,34 blood samples and 83 FFPE tissue samples (including the 34 patients with available blood samples) were collected. DNA was extracted from 34 blood samples (9 males and 25 females) and 30 FFPE tissue samples (13 males and 17 females).
Part 2:Genetic assay of SDH genes for point mutations.
We designed primers for all of the SDHB, SDHC and SDHD exons according to our requirements. Genetic assays were done for 64 HNPGL patients. Each exon of SDH genes was amplified and direct sequenced. By sequence BLASTing, we revealed that 48.5% of the 64 patients carry SDH mutations (10 SDHB mutations,3 SDHC mutations and 18 SDHD mutations) and 9 novel mutations were identified.
Part 3:Large deletion detection for SDH genes
For the 33 patients without any mutation of SDH genes, we detect the large deleton of SDH genes by multiplex ligation-dependent probe amplification. None of these patient was revealed to carry a SDH gene copy number variant.
Part 4:Haplotype analysis of patients with a same mutation
Three chinese patients were reported to carry the SDHD c.3G>C mutation and another 2 patients with this mutation were identified in our study. We constructed the haplotype for 4 of the 5 families and compared the STR combinations between the families. We also calculated the probabilities of the STR combinations shared by these families in a control group of 75 blood donors and the result showed that the same mutation shared by these families are due to a founder effect.
Conclusion:There are 48.5% of the 64 patients carrying SDH mutations, including 10 SDHB mutations,3 SDHC mutations and 18 SDHD mutations. Nine novel mutations were identified. None was found to carry a SDHAF2 gene mutation or copy number variant. SDHD c.3G>C mutation is due to a founder effect.
本研究共分为四个部分：
第一部分头颈部副神经节瘤患者临床资料和DNA样本的搜集
本部分研究工作查阅自2002年至今在我院经手术治疗后病理证实为副神经节瘤患者病历,设计临床信息登记表,联系患者进行回访,并邀请其参与本研究。在获得知情同意后,详细完善临床资料及家系情况,获取患者血样并提取DNA备用。对近期手术的患者以及研究阶段新入院的患者,在复查随访和术后阶段亦纳入本研究中。同时,从病理科调取所有患者的肿瘤组织石蜡包埋肿瘤组织标本,提取DNA备用。共搜集头颈部副神经节瘤患者血样34例,石蜡包埋组织样本83例(含34例已获取血样的患者)。提取了34例患者的血样DNA(男性9例、女性25例)和30例患者(男性13例、女性17例)的石蜡包埋组织样本DNA。
第二部分琥珀酸脱氢酶基因点突变检测
本部分研究对64例头颈部副神经节瘤患者的DNA样本进行了SDHB、SDHC、SDHD和SDHAF2基因突变检测。根据实验需要设计SDHB、SDHC和SDHD基因各外显子扩增引物(SDHAF2使用文献引物),经PCR扩增后行序列分析。BLAST序列对比找出SDH基因突变,并通过基因突变数据库对比、突变类型分析、突变位点物种保守性分析等方法,判断其致病性。对特殊突变通过PCR扩增子质粒克隆及单克隆测序分析进行进一步验证。
本部分研究发现48.5%(31／64)的患者携带有SDHB (10例)、SDHC (3例)或SDHD(18例)基因突变,3者的检出率分别为16%、5%和28%,未发现有患者携带SDHAF2基因突变。其中发现了9种新突变,部分结果已提交至SDH突变数据并可在线查询。34例获取了静脉血样的患者中,61.7%(21／34)携带有SDH基因突变(SDHB7例,SDHC 3例,SDHD 11例)；30例检测肿瘤石蜡包埋组织样本DNA的患者中,仅33.3%(10／30)发现携带有SDH基因突变(SDHB 4例,SDHD 7例),小于静脉血样组,p＜0.005。
6例家族性患者均携带SDHD基因突变,占携带SDHD突变的患者总数的33%(6／18),6例多发肿瘤患者亦均为SDHD突变携带者,其中3例为家族性发病患者。2例恶性肿瘤患者均携带有SDH突变,SDHB和SDHD各1例。
第三部分琥珀酸脱氢酶基因大片段缺失检测
本研究对PCR扩增直接测序未发现有突变的33例患者运用多重连接依赖式探针扩增技术对SDH基因的各外显子进行了拷贝数异常检测。未发现有患者的SDH基因拷贝数有异常,说明无染色体重排引起的SDH基因区域大片段缺失。
第四部分多发突变的单体型分析和创始者效应分析
对SDHD基因中出现的多发突变,通过构建各家系的微卫星单体型并将各患者的单体型进行比较,发现携带SDHD c.3G>C突变的4例患者中,有3个患者有相同的微卫星等位基因组合。在75例正常人群中统计了各等位基因的频率,判断他们共享的等位基因组合在正常人群中的概率仅2×10-8～5×10-5,4个不相关的家系同时携带此组合的几率则更小,因此考虑该基因突变为创始者效应所致。
总结：研究发现64例头颈部副神经节瘤患者中48.5%携带有SDH基因突变,包括10例SDHB、3例SDHC和18例SDHD基因突变,其中9种为新突变。没有发现患者携带SDHAF2基因突变；多重连接依赖式探针扩增法没有在患者中发现有SDH基因大片段缺失；单体型分析证实了一个中国患者中的多发突变SDHD c.3G>C为创始者突变。
Paragangliomas are rare tumors occurring at head and neck area. Recently, it has been revealed that paragangliomas have a relationship with germline mutations of succinate dehydrogenase encoding genes. To evaluate the role and characteristics of SDH gene mutations in Chinese patients, we collected DNA samples of familiar and sporadic patients with head and neck paraganliomas and screened for germline mutations. We also analyzed the pathogenicity of the mutations and genotyped the haplotypes of the patients with same mutations.
The study consists of 4 portions:
Part 1:Collection of clinical data and DNA samples of HNPGL patients
We recalled the case records on PGL and select the HNPGL cases confirmed by pathologic diagnosis. We contacted the patients and informed them about our study. With their consents, we registered their detailed clinical and familiar information and we collected blood samples from every patient and the formalin-fixed and paraffin-embedded (FFPE) tissue samples from the department of Pathology. In total,34 blood samples and 83 FFPE tissue samples (including the 34 patients with available blood samples) were collected. DNA was extracted from 34 blood samples (9 males and 25 females) and 30 FFPE tissue samples (13 males and 17 females).
Part 2:Genetic assay of SDH genes for point mutations.
We designed primers for all of the SDHB, SDHC and SDHD exons according to our requirements. Genetic assays were done for 64 HNPGL patients. Each exon of SDH genes was amplified and direct sequenced. By sequence BLASTing, we revealed that 48.5% of the 64 patients carry SDH mutations (10 SDHB mutations,3 SDHC mutations and 18 SDHD mutations) and 9 novel mutations were identified.
Part 3:Large deletion detection for SDH genes
For the 33 patients without any mutation of SDH genes, we detect the large deleton of SDH genes by multiplex ligation-dependent probe amplification. None of these patient was revealed to carry a SDH gene copy number variant.
Part 4:Haplotype analysis of patients with a same mutation
Three chinese patients were reported to carry the SDHD c.3G>C mutation and another 2 patients with this mutation were identified in our study. We constructed the haplotype for 4 of the 5 families and compared the STR combinations between the families. We also calculated the probabilities of the STR combinations shared by these families in a control group of 75 blood donors and the result showed that the same mutation shared by these families are due to a founder effect.
Conclusion:There are 48.5% of the 64 patients carrying SDH mutations, including 10 SDHB mutations,3 SDHC mutations and 18 SDHD mutations. Nine novel mutations were identified. None was found to carry a SDHAF2 gene mutation or copy number variant. SDHD c.3G>C mutation is due to a founder effect.
引文
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[4]Hao HX, Khalimonchuk 0, Schraders M, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science,2009,325:1139-1142.
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[1]Badenhop RF, Cherian S, Lord RS, et al. Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss. Genes Chromosomes Cancer,2001,31:255-263.
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[10]Mannelli, M., et al., SDH mutations in patients affected by paraganglioma syndromes:a personal experience. Ann N Y Acad Sci,2006.1073: p.183-9
[11]Simi L, Sestini R, Ferruzzi P, et al. Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X. J Med Genet,2005,42:e52
[12]Peczkowska, M., et al., Impact of screening kindreds for SDHD p. Cys11X as a common mutation associated with paraganglioma syndrome type 1. J Clin Endocrinol Metab,2008.93(12):p.4818-25.
[13]Baysal, B.E., et al., An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma. Journal of Medical Genetics,2004. 41(9):p.703-9.
[14]Badenhop RF, Jansen JC, Fagan PA, et al. The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features. J Med Genet,2004,41:e99.
[15]Astuti D, Hart-Holden N, Latif F, et al. Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. Clin Endocrinol (Oxf),2003,59:728-733.
[16]Isobe K, Minowada S, Tatsuno I, et al. Novel germline mutations in the SDHB and SDHD genes in Japanese pheochromocytomas. Horm Res,2007,68:68-71.
[1]Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.Science,2000, 287:848-851.
[2]Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet,2000,26:268-270.
[3]Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J of Hum Genet,2001, 69:49-54.
[4]Horvath R, Abicht A, Holinski-Feder E, et al. Leigh syndrome caused by mutations in the flavoprotein(Fp) subunit of succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry,2006,77:74-76.
[5]Hao HX, Khalimonchuk 0, Schraders M, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science,2009,325:1139-1142.
[6]Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA, 2004,292:943-951.
[7]Gimm 0, Armanios M, Dziema H, et al. Somatic and occult germ-line mutations in SDHD, a mitochondrial complex Ⅱ gene, in nonfamilial pheochromocytoma. Cancer Res,2000,60:6822-6825.
[8]Korpershoek E, Petri BJ, van Nederveen FH, et al. Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma. Endocr Relat Cancer,2007,14:453-462.
[9]van Nederveen FH, Korpershoek E, Lenders JW, et al. Somatic SDHB mutation in an extraadrenal pheochromocytoma. N Engl J Med,2007,357:306-308.
[10]Hensen EF, Jordanova ES, van Minderhout IJ, et al. Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families. Oncogene,2004, 23:4076-4083.
[11]Douwes Dekker PB, Corver WE, Hogendoorn PC, et al. Multiparameter DNA flow-sorting demonstrates diploidy and SDHD wild-type gene retention in the sustentacular cell compartment of head and neck paragangliomas:chief cells are the only neoplastic component. J Pathol,2004,202:456-462.
[12]Pigny P, Vincent A, Cardot Bauters C, et al. Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. J Clin Endocrinol Metab,2008,93:1609-1615.
[13]Taschner PE, Jansen JC, Baysal BE, et al. Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene. Genes Chromosomes Cancer,2001,31:274-281.
[14]Dannenberg H, Dinjens WN, Abbou M, et al. Frequent germ-line succinate dehydrogenase subunit D gene mutations in patients with apparently sporadic parasympathetic paraganglioma. Clin Cancer Res,2002,8:2061-2066.
[15]Bayley JP, van Minderhout I, Weiss MM, et al. Mutation analysis of SDHB and SDHC:novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma. BMC Med Genet,2006, 7:1.
[16]Bayley JP, Grimbergen AE, van Bunderen PA, et al. The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients. BMC Med Genet, 2009,10:34.
[17]Bayley JP, Weiss MM, Grimbergen A, et al. Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients. Endocr Relat Cancer,2009,16:929-937.
[18]Baysal BE, Willett-Brozick JE, Lawrence EC, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet,2002,39:178-183.
[19]Baysal BE, Willett-Brozick JE; Filho PA, et al. An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma. J Med Genet,2004, 41:703-709.
[20]Milunsky JM, Maher TA, Michels VV, et al. Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma. Am J Med Genet,2001,100:311-314.
[21]Mhatre. AN, Li Y, Feng L, et al. SDHB, SDHC, and SDHD mutation screen in sporadic and familial head and neck paragangliomas. Clin Genet,2004, 66:461-466.
[22]McWhinney SR, Pilarski RT, Forrester SR, et al. Large germline deletions of mitochondrial complex II subunits SDHB and SDHD in hereditary paraganglioma. J Clin Endocrinol Metab,2004,89:5694-5699.
[23]Boedeker CC, Neumann HP, Maier W, et al. Malignant head and neck paragangliomas in SDHB mutation carriers. Otolaryngol Head Neck Surg,2007, 137:126-129.
[24]Neumann HP, Erlic Z, Boedeker CC, et al. Clinical predictors for germline mutations in head and neck paraganglioma patients:cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res,2009,69: 3650-3656.
[25]Burnichon N, Rohmer V, Amar L, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab,2009,94:2817-2827.
[26]Mannelli M, Castellano M, Schiavi F, et al. Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab, 2009,94:1541-1547.
[27]Simi L, Sestini R, Ferruzzi P, et al. Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X. J Med Genet,2005,42:e52.
[28]Badenhop RF, Jansen JC, Fagan PA, et al. The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features. J Med Genet,2004,41:e99.
[29]Lima J, Fei jao T, Ferreira da Silva A, et al. High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain:mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathological correlations. J Clin Endocrinol Metab,2007,92:4853-4864.
[30]Persu A, Hamoir M, Gregoire V, et al. High prevalence of SDHB mutations in head and neck paraganglioma in Belgium. J Hypertens,2008,26:1395-1401.
[31]Cascon A, Pita G, Burnichon N, et al. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab,2009,94: 1701-1705.
[32]Cascon A, Landa I, Lopez-Jimenez E, et al. Molecular characterisation of a common SDHB deletion in paraganglioma patients. J Med Genet,2008,45: 233-238.
[33]Astuti D, Hart-Holden N, Latif F, et al. Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. Clin Endocrinol (Oxf),2003,59:728-733.
[34]Armstrong R, Greenhalgh KL, Rattenberry E, et al. Succinate dehydrogenase subunit B (SDHB) gene deletion associated with a composite paraganglioma/neuroblastoma. J Med Genet,2009,46:215-216.
[35]Badenhop RF, Cherian S, Lord RS, et al. Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss. Genes Chromosomes Cancer,2001,31:255-263.
[36]Lee SC, Chionh SB, Chong SM, et al. Hereditary paraganglioma due to the SDHD M1I mutation in a second Chinese family:a founder effect? Laryngoscope,2003,113:1055-1058.
[37]Ma RC, Lam CW, Chan WB, et al. A Chinese family with familial paraganglioma syndrome due to succinate dehydrogenase deficiency. Hong Kong Med J,2007,13:151-154.
[38]吕伟明,刘瑞磊,李杰,等.琥珀酸脱氢酶基因突变与颈动脉体瘤发病机制研究.中华实验外科杂志,2008,25：1254-1256.
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[41]Baysal BE. Hereditary paraganglioma targets diverse paraganglia. J Med Genet,2002,39:617-622.
[42]Astrom K, Cohen JE, Willett-Brozick JE, et al. Altitude is a phenotypic modifier in hereditary paraganglioma type 1:evidence for an oxygen-sensing defect. Hum Genet,2003,113:228-237.
[43]Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol,2005,23: 8812-8818.
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[45]Amar L, Baudin E, Burnichon N, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab,2007,92:3822-3828.
[46]Havekes B, Corssmit EP, Jansen JC, et al. Malignant paragangliomas associated with mutations in the succinate dehydrogenase D gene. J Clin Endocrinol Metab,2007,92:1245-1248.
[47]Timmers HJ, Pacak K, Bertherat J, et al. Mutations associated with succinate dehydrogenase D-related malignant paragangliomas. Clin Endocrinol(Oxf),2008,68:561-566.
[48]Solis DC, Burnichon N, Timmers HJ, et al. Penetrance and clinical consequences of a gross SDHB deletion in a large family. Clin Genet,2009, 75:354-363.
[49]Peczkowska M, Erlic Z, Hoffmann MM, et al. Impact of screening kindreds for SDHD p. Cys11X as a common mutation associated with paraganglioma syndrome type 1. J Clin Endocrinol Metab,2008,93:4818-4825.
[50]Schiavi F, Boedeker CC, Bausch B, et al. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. JAMA, 2005,294:2057-2063.
[51]Niemann S, Muller U, Engelhardt D, et al. Autosomal dominant malignant and catecholamine-producing paraganglioma caused by a splice donor site mutation in SDHC. Hum Genet,2003,113:92-94.
[52]Pasini B, McWhinney SR, Bei T, et al. 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. Eur J Hum Genet,2008,16:79-88.
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[54]Peczkowska M, Cascon A, Prejbisz A, et al. Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. Nat Clin Pract Endocrinol Metab,2008,4:111-115.
[2]Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex Ⅱ gene, in hereditary paraganglioma. Science,2000, 287:848-851.
[3]Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genetics,2000,26:268-270.
[4]Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. American Journal of Human Genetics,2001,69:49-54.
[5]Horvath R, Abicht A, Holinski-Feder E, et al. Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). Journal of Neurology, Neurosurgery and Psychiatry,2006,77:74-76.
[6]Hao HX, Khalimonchuk 0, Schraders M, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science,2009,325:1139-1142.
[7]Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA,2004,292:943-951.
[8]Neumann HP, Erlic Z, Boedeker CC, et al. Clinical predictors for germline mutations in head and neck paraganglioma patients:cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res,2009,69:3650-3656.
[9]Burnichon N, Rohmer V, Amar L, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab,2009.
[10]Cascon A, Pita G, Burnichon N, et al. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab,2009,94: 1701-1705.
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[1]Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex Ⅱ gene, in hereditary paraganglioma. Science,2000, 287:848-851.
[2]Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genetics,2000,26:268-270.
[3]Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility, to familial pheochromocytoma and to familial paraganglioma. American Journal of Human Genetics,2001,69:49-54.
[4]Hao HX, Khalimonchuk 0, Schraders M, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science,2009,325:1139-1142.
[5]Hensen EF, Jordanova ES, van Minderhout IJ, et al. Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families. Oncogene,2004, 23:4076-4083.
[6]Mannelli M, Castellano M, Schiavi F, et al. Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab, 2009,94:1541-1547.
[7]Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA,2004,292:943-951.
[8]Neumann HP, Erlic Z; Boedeker CC, et al. Clinical predictors for germline mutations in head and neck paraganglioma patients:cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res,2009,69:3650-3656.
[9]Burnichon N, Rohmer V, Amar L, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab,2009.
[10]Cascon A, Pita G, Burnichon N, et al. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab,2009,94: 1701-1705.
[11]Lee SC, Chionh SB, Chong SM, et al. Hereditary paraganglioma due to the SDHD M1I mutation in a second Chinese family:a founder effect? Laryngoscope,2003,113:1055-1058.
[12]Ma RC, Lam CW, Chan WB, et al. A Chinese family with familial paraganglioma syndrome due to succinate dehydrogenase deficiency. Hong Kong Med J,2007,13:151-154.
[13]Watanabe H, Burnstock G, Jarrott B, et al. Mitochondrial abnormalities in human phaeochromocytoma. Cell Tissue Res,1976,172:281-288.
[14]吕伟明,刘瑞磊,李杰,et a1.琥珀酸脱氢酶基因突变与颈动脉体瘤发病机制研究.中华实验外科杂志,2008,25：1254-1256.
[15]Peczkowska M, Erlic Z, Hoffmann MM, et al. Impact of screening kindreds for SDHD p.Cys11X as a common mutation associated with paraganglioma syndrome type 1. J Clin Endocrinol Metab,2008,93:4818-4825.
[16]Horvath R, Abicht A, Holinski-Feder E, et al. Leigh syndrome caused by mutations in the flavoprotein(Fp) subunit of succinate dehydrogenase(SDHA). J Neurol Neurosurg Psychiatry,2006,'77:74-76.
[1]Bryan MA, Cheng H, Brodsky B. Sequence environment of mutation affectsstability and folding in collagen model peptides of osteogenesis imperfecta. Biopolymers.2010 Mar 16.
[2]Astrom K, Cohen JE, Willett-Brozick JE, et al. Altitude is a phenotypic modifier in hereditary paraganglioma type 1:evidence for an oxygen-sensing defect. Hum Genet,2003,113:228-237.
[3]Jech M, Alvarado-Cabrero I, Albores-Saavedra J, et al. Genetic analysis of high altitude paragangliomas. Endocr Pathol,2006,17:201-202.
[1]Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res.2002 Jun 15;30(12):e57.
[2]Wang X, Wang Z, Yan M, Huang S, Chen TJ, Zhong N. Similarity of DMD gene deletion and duplication in the Chinese patients compared to global populations. Behav Brain Funct.2008 Apr 29; 4:20.
[3]Lorson CL, Rindt H, Shababi M. Spinal muscular atrophy:mechanisms and therapeutic strategies. Hum Mol Genet.2010 Apr 28.
[4]Del Valle J, Feliubadalo L, Nadal M, Teule A, Mir6 R, Cuesta R, Tornero E, Menendez M, Darder E, Brunet J, Capella G, Blanco I, Lazaro C. Identification and comprehensive characterization of large genomic rearrangements in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat.2009 Nov 6.
[5]Bayley JP, Grimbergen AE, van Bunderen PA, et al. The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients. BMC Med Genet, 2009,10:34.
[6]Bayley JP, Weiss M, Grimbergen A, et al. Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients. Endocr Relat Cancer,2009,16:929-937.
[7]Cascon A, Pita G, Burnichon N, et al. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab,2009,94: 1701-1705.
[8]Cascon A, Landa I, Lopez-Jimenez E, et al. Molecular characterisation of a common SDHB deletion in paraganglioma patients. Journal of Medical Genetics,2008,45:233-238.
[9]McWhinney SR, Pilarski RT, Forrester SR, et al. Large germline deletions of mitochondrial complex Ⅱ subunits SDHB and SDHD in hereditary paraganglioma. J Clin Endocrinol Metab,2004,89:5694-5699.
[10]Armstrong R, Greenhalgh KL, Rattenberry E, et al. Succinate dehydrogenase subunit B (SDHB) gene deletion associated with a composite paraganglioma/neuroblastoma. J Med Genet,2009,46:215-216.
[11]Solis DC, Burnichon N, Timmers HJ, et al. Penetrance and clinical consequences of a gross SDHB deletion in a large family. Clin Genet,2009, 75:354-363.
[1]Badenhop RF, Cherian S, Lord RS, et al. Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss. Genes Chromosomes Cancer,2001,31:255-263.
[2]Lee SC, Chionh SB, Chong SM, et al. Hereditary paraganglioma due to the SDHD M1I mutation in a second Chinese family:a founder effect? Laryngoscope, 2003,113:1055-1058.
[3]Ma RC, Lam CW, Chan WB, et al. A Chinese family with familial paraganglioma syndrome due to succinate dehydrogenase deficiency. Hong Kong Med J,2007,13:151-154.
[4]Baysal BE, Willett-Brozick JE, Lawrence EC, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet,2002,39:178-183.
[5]Taschner PE, Jansen JC, Baysal BE, et al. Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene. Genes Chromosomes Cancer,2001,31:274-281.
[6]Dannenberg H,'Dinjens WN, Abbou M, et al. Frequent germ-line succinate dehydrogenase subunit D gene mutations in patients with apparently sporadic parasympathetic paraganglioma. Clinical Cancer Research,2002,8: 2061-2066.
[7]Bayley JP, Grimbergen AE, van Bunderen PA, et al. The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients. BMC Med Genet, 2009,10:34.
[8]Cascon, A., et al., Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab,2009.94(5):p.1701-5.
[9]Cascon, A., et al., Molecular characterisation of a common SDHB deletion in paraganglioma patients. Journal of Medical Genetics,2008.45(4):p. 233-8.
[10]Mannelli, M., et al., SDH mutations in patients affected by paraganglioma syndromes:a personal experience. Ann N Y Acad Sci,2006.1073: p.183-9
[11]Simi L, Sestini R, Ferruzzi P, et al. Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X. J Med Genet,2005,42:e52
[12]Peczkowska, M., et al., Impact of screening kindreds for SDHD p. Cys11X as a common mutation associated with paraganglioma syndrome type 1. J Clin Endocrinol Metab,2008.93(12):p.4818-25.
[13]Baysal, B.E., et al., An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma. Journal of Medical Genetics,2004. 41(9):p.703-9.
[14]Badenhop RF, Jansen JC, Fagan PA, et al. The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features. J Med Genet,2004,41:e99.
[15]Astuti D, Hart-Holden N, Latif F, et al. Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. Clin Endocrinol (Oxf),2003,59:728-733.
[16]Isobe K, Minowada S, Tatsuno I, et al. Novel germline mutations in the SDHB and SDHD genes in Japanese pheochromocytomas. Horm Res,2007,68:68-71.
[1]Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.Science,2000, 287:848-851.
[2]Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet,2000,26:268-270.
[3]Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J of Hum Genet,2001, 69:49-54.
[4]Horvath R, Abicht A, Holinski-Feder E, et al. Leigh syndrome caused by mutations in the flavoprotein(Fp) subunit of succinate dehydrogenase (SDHA). J Neurol Neurosurg Psychiatry,2006,77:74-76.
[5]Hao HX, Khalimonchuk 0, Schraders M, et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science,2009,325:1139-1142.
[6]Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA, 2004,292:943-951.
[7]Gimm 0, Armanios M, Dziema H, et al. Somatic and occult germ-line mutations in SDHD, a mitochondrial complex Ⅱ gene, in nonfamilial pheochromocytoma. Cancer Res,2000,60:6822-6825.
[8]Korpershoek E, Petri BJ, van Nederveen FH, et al. Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma. Endocr Relat Cancer,2007,14:453-462.
[9]van Nederveen FH, Korpershoek E, Lenders JW, et al. Somatic SDHB mutation in an extraadrenal pheochromocytoma. N Engl J Med,2007,357:306-308.
[10]Hensen EF, Jordanova ES, van Minderhout IJ, et al. Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families. Oncogene,2004, 23:4076-4083.
[11]Douwes Dekker PB, Corver WE, Hogendoorn PC, et al. Multiparameter DNA flow-sorting demonstrates diploidy and SDHD wild-type gene retention in the sustentacular cell compartment of head and neck paragangliomas:chief cells are the only neoplastic component. J Pathol,2004,202:456-462.
[12]Pigny P, Vincent A, Cardot Bauters C, et al. Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. J Clin Endocrinol Metab,2008,93:1609-1615.
[13]Taschner PE, Jansen JC, Baysal BE, et al. Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene. Genes Chromosomes Cancer,2001,31:274-281.
[14]Dannenberg H, Dinjens WN, Abbou M, et al. Frequent germ-line succinate dehydrogenase subunit D gene mutations in patients with apparently sporadic parasympathetic paraganglioma. Clin Cancer Res,2002,8:2061-2066.
[15]Bayley JP, van Minderhout I, Weiss MM, et al. Mutation analysis of SDHB and SDHC:novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma. BMC Med Genet,2006, 7:1.
[16]Bayley JP, Grimbergen AE, van Bunderen PA, et al. The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients. BMC Med Genet, 2009,10:34.
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