Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-α binding site missense mutations elevate age-specific risk for CNS hemangioblastoma.
Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-α binding site missense mutations elevate age-specific risk for CNS hemangioblastoma.
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DOI：
10.1186/s12881-016-0306-2
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发表时间：
2016-07-20
影响因子：
--
通讯作者：
Seong MW
中科院分区：
文献类型：
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作者：
Lee JS;Lee JH;Lee KE;Kim JH;Hong JM;Ra EK;Seo SH;Lee SJ;Kim MJ;Park SS;Seong MW
von Hippel-Lindau (VHL) 病是一种由 VHL 基因突变引起的罕见遗传性肿瘤综合征，其特征为异质表型，如中枢神经系统、视网膜、肾脏、肾上腺和胰腺的良性/恶性肿瘤。迄今为止，韩国人群的基因型与表型相关性尚未得到很好的表征。因此，本研究旨在评估韩国 VHL 患者的 VHL 突变谱和基因型-表型相关性。包括 13 名具有 VHL 突变的无关受试者。进行直接测序和多重连接依赖性探针扩增。因此，评估了受试者的临床表现和家族史。我们鉴定了 10 种不同的 VHL 突变。 c.160_161delAT 移码突变是新颖的。错义突变聚集在 2 个结构域（外显子 1 中的 α 结构域；外显子 3 中的 β 结构域）。最常见的突变是 c.208G > A (p.Glu70Lys)。在具有新生突变的受试者中观察到较温和的表型。在 HIF-α 结合位点内携带错义突变的受试者中，中枢神经系统血管母细胞瘤的年龄特异性风险显着较高（P<0.05）。这项研究提供了对基因型-表型相关性的深入了解，因为 HIF-α 结合位点的氨基酸取代可能使患者易患与年龄相关的中枢神经系统血管母细胞瘤风险。
von Hippel-Lindau (VHL) disease is a rare hereditary tumor syndrome caused by VHL gene mutations that is characterized by heterogeneous phenotypes such as benign/malignant tumors of the central nervous system, retina, kidney, adrenal gland, and pancreas. The genotype-phenotype correlation has not been well characterized in the Korean population so far. Therefore, this study aimed to evaluate the VHL mutation spectrum and genotype-phenotype correlations in Korean VHL patients. Thirteen unrelated subjects with VHL mutations were included. Direct sequencing and multiplex ligation-dependent probe amplification were performed. Consequently, the clinical manifestations and family histories of the subjects were evaluated. We identified 10 different VHL mutations. The c.160_161delAT frameshift mutation was novel. Missense mutations clustered in 2 domains (α domain in exon 1; β domain in exon 3). The most frequently observed mutation was c.208G > A (p.Glu70Lys). Milder phenotypes were observed in subjects with de novo mutations. Age-specific risk for CNS hemangioblastoma was significantly higher in subjects carrying missense mutations within the HIF-α binding site (P < 0.05). This study provides insight into the genotype-phenotype correlation in that amino acid substitutions in the HIF-α binding site may predispose patients to age-related risks of CNS hemangioblastoma.