VHL基因新突变致VHL综合征伴脑膜瘤一家系分析

Novel VHL gene variant mutation of von Hippel-Lindau disease with right frontal meningioma:one pedigree study

目的:对1例von Hippel-Lindau(VHL)综合征2C型合并右额叶脑膜瘤患者及其家系的临床特征、基因突变进行分析,通过蛋白功能预测和文献复习探讨脑膜瘤与VHL综合征的关系。方法:对患者的临床表型进行分析,应用Sanger测序技术对患者外周血及病理组织切片进行VHL基因全部编码区测序,收集患者家属的临床资料,对突变位点进行验证。结果:患者表现为双侧肾上腺和腹膜后嗜铬细胞瘤、左眼视网膜毛细血管瘤和右额叶脑膜瘤,基因检测发现VHL基因第一外显子存在c.284C>G(p.Pro 95 Arg)错义突变,家系验证显示其临床表型正常的父母和一女均未携带该变异,另一临床表型正常的女儿携带该变异,说明该变异为患者的新生变异。通过错义突变蛋白功能预测软件Polyphen-2和氨基酸多序列对比工具(Clustal W)及蛋白质3D图对该突变进行功能预测显示该突变是功能突变,对VHL的活性具有潜在显著影响,与临床表型关系显著。结论:VHL基因的c.284C>G变异可能是该患者罹患VHL综合征的遗传学病因,导致嗜铬细胞瘤和视网膜毛细血管瘤的发生。

Aim:To analyze the clinical features and genetic variations of a patient with von Hippel-Lindau(VHL)disease type 2C complicated with right frontal lobe meningioma and his family,and to discuss the association of the novel VHL genetic variation with meningioma and VHL disease by predicting effects of the genetic variations on protein function and literature review.Methods:The clinical phenotypes of the patient were analyzed.Sanger sequencing was used to sequence all the coding regions of VHL gene in DNA extracted from the peripheral blood and meningioma pathological tissue sections of the patient,and clinical data of his family were collected and the variant was verified in them.Results:The patient presented with bilateral adrenal pheochromocytoma and retroperitoneal pheochromocytoma,retinal angioma of the left eye,and meningioma of the right frontal lobe.A novel variant c.284C>G(p.Pro 95 Arg)was observed in exon 1 of VHL gene.His parents and one daughter with normal clinical phenotype did not carry the variant,but another daughter with normal clinical phenotype was carrying the variant,which indicated that the mutation was a novel variant of the patient.Functional prediction of the mutation was performed by means of the missense mutant protein function prediction software Polyphen-2,amino acid multiple sequence comparison tool(Clustal W)and protein 3D diagram,which showed that the mutation was a functional mutation with a potentially significant influence on the activity of VHL and was closely related to the clinical phenotype.Conclusion::The novel variant VHLc.284C>G might be the genetic determinant of VHL disease in this patient,leading to pheochromocytoma and retinal angioma.