Associations between VHL genotype and clinical phenotype in familial von Hippel-Lindau disease
Associations between VHL genotype and clinical phenotype in familial von Hippel-Lindau disease
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DOI：
10.1111/j.1365-2362.2007.01806.x
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发表时间：
2007-06-01
影响因子：
5.5
通讯作者：
Lin, C. M.
中科院分区：
文献类型：
--
作者：
Huang, J. S.;Huang, C. J.;Lin, C. M.
背景：Von Hippel-Lindau病(VHL)是一种常染色体显性遗传性疾病，与中枢神经系统(CNS)和其他内脏器官的肿瘤和囊肿性疾病有关。染色体3p25-26上VHL基因的胚系突变被认为是该病的原因。材料与方法我们研究了6例VHL病患者及其亲属。杂合性缺失(LOH)由VHL基因座上的5个侧翼微卫星多态标记确定。采用多重连接依赖探针扩增(MLPA)和实时定量聚合酶链式反应(QPCR)检测基因组缺失。结果发现vhl基因有3个种系缺失，分别为142.9、53.3和3.3kb。这些缺失通过qPCR分析得到了明确的定义。142.9kb的生殖系缺失与中枢神经系统血管母细胞瘤患者显著相关(经Fisher‘s精确检验P<；0.01)，在同一家系中的一个胰腺囊肿患者中检测到一个错义突变(Gln209Arg)。1例双侧肾细胞癌患者也检测到LOH。结论不同的遗传状态与VHL病的临床表现有关。MLPA或qPCR可检测到的基因组缺失是导致该综合征的主要原因。错义突变和杂合性缺失会导致复杂的临床症状，而基因分型可以帮助临床诊断，因为它们有很强的相关性。
Background Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary disorder associated with tumours and cysts in the central nervous system (CNS) and other visceral organs. Germline mutations in the VHL gene on chromosome 3p25-26 are considered the cause of this disease.Materials and methods We studied six patients with VHL disease and their relatives. Loss of heterozygosity (LOH) was determined by five flanking microsatellite polymorphic markers in the VHL locus. Multiplex ligation-dependent probe amplification (MLPA) and quantitative real-time polymerase chain reaction (qPCR) amplification were used to detect the genomic deletions. Single-strand conformation polymorphism (SSCP) analysis was applied to test for sequence variations.Results Three germline deletions in the VHL gene (142.9, 53.3 and 3.3 kb) were found by MLPA. These deletions were defined clearly by qPCR analyses. The142.9 kb germline deletion was significantly associated with patients with CNS haemangioblastomas (P < 0.01 by Fisher's exact test), and one missense mutation (Gln209Arg) was detected from a patient with a pancreatic cyst in the same family. LOH was also detected from a patient with bilateral renal cell carcinomas.Conclusion Diverse genetic conditions are associated with the clinical manifestations of VHL disease. Genomic deletions that can be detected by MLPA or qPCR are major causes for this syndrome. Missense mutations and LOH accompanying the disease lead to complex clinical symptoms and genotypic determination can facilitate a clinical diagnosis because of their strong association.