遗传性出血性毛细血管扩张症相关ACVRL1基因新突变——c.1246+5G>C

A novel mutation of ACVRL1(c.1246+5G>C)associated with hereditary hemorrhagic telangiectasia

目的遗传性出血性毛细血管扩张症(hereditary hemorrhagic telangiectasia,HHT)是一种遗传性系统性血管性疾病。本研究拟对1例HHT家系先证者临床特征及致病基因进行分析。方法收集1例HHT家系先证者,对其行表型和基因突变进行分析。应用PCR扩增测序的方法对该病相关基因全部编码区进行序列分析,并应用NetGene2和minigene方法对发现的变异功能进行分析。结果先证者具有鼻出血、皮肤毛细血管扩张及家族史,符合HHT诊断;基因检测发现ACVRL1基因c.1246+5G>C变异,为未报道的新突变。NetGene2软件分析发现其可影响外显子8的剪接。Minigene分析发现突变型在转录时外显子8被略过,导致ACVRL1基因功能异常。结论本研究在1例HHT家系中发现ACVRL1基因外显子8附近一个新突变—c.1246+5G>C,支持ACVRL1基因外显子8区域为中国HHT的突变热点。

OBJECTIVE Hereditary hemorrhagic telangiectasia(HHT)is a vascular dysplasia disorder characterized by epistaxis,mucocutaneous telangiectasias,arteriovenous malformations in internal organs and family history.This study analyzed the clinical and genetic characters of a proband from a family with HHT.The function and the pathogenicity of the mutation was analyzed.METHODS Clinical and genetic characters for the proband were analyzed.The coding region and the flanking sequenses of ENG,ACVRL1.SMAD4 and BMP9 were analyzed aplying the polymerase chain reaction(PCR)and sequencing.Further pathogenic analysis were performed using the NetGene2 and minigene.RESULTS We recruited a HHT family from Jiangsu Province.The proband was diagnosed with the recurrent epistaxis,mucocutaneous telangiectasias,arteriovenous malformations and family history.Genetic testing founnd a novel variant(c.1246+5 G>C)in the intron 8 of ACVRL1,which may affect the splicing of exon 8 according to the prediction using NetGene2.Minigene constructs confirmed c.1246+5 G>C causeds exon8 skipping in cell line,which was expected to cause loss of ACVRL1 function.CONCLUSION A novel mutaion was found in near the exon8 of ACVRL1 gene,and the function and the pathogenicity were confirmed.These results further supported the previous point that the exon 8 of ACVRL1 may be the hotspot region for the HHT from Chinese.