Objective: To investigate the clinical feature of a family with hereditary hemorrhagic telangiectasia (HHT), and to study the mutation of its related genes.
Methods: Medical histories of the family were analyzed to detect HHT patients according to the diagnostic criteria. ENG and ALK-1 genes of the proband and her two daughters were analyzed. DNA from the three patients' peripheral blood was extracted. The exons 2-10 and their intron-exon boundaries of ALK1 were amplified with PCR, and then the PCR products were sequenced and analyzed to identify the mutation.
Results: There were 11 people in 41 family members of 4 generations were diagnosed as HHT. The proband and her two daughters suffered from multiple organ damage, the younger daughter appeared only imaging features instead of corresponding clinical symptoms. A missense mutation at the 1321 bp of cDNA (c.1321G>A) was detected in the exon 9 of ALK1, which resulted in valine 441 to methionine replacement in ALK-1 protein (p.Val441Met).
Conclusion: A Chinese family with HHT was studied and a missense mutation (c.1321G>A, p.Val441Met) of ALK-1 was discovered. This mutation is the genetic basis of the family with HHT and is reported for the first time in China. This research will not only help to further investigate molecular mechanism of pathogenesis of HTT, but also provide evidences and references for the following gene screening and genetic counseling on HTT family members.
目的: 研究一个遗传性出血性毛细血管扩张症（HHT）家系的ENG基因及ALK-1基因的突变情况，探讨其分子发病机制。
方法: 采集该HHT家系患者的临床资料，按照HHT的临床诊断标准进行确诊，对先证者及其确诊为HHT的2个女儿进行ENG基因和ALK-1基因筛查。采集母女3人的外周血标本，提取基因组DNA，用聚合酶链反应(PCR)扩增DNA标本中ALK-1基因的2、3、4、5、6、7、8、9、10外显子及周围内含子，并对PCR产物纯化后进行核苷酸测序，确定突变位点。
结果: 该家系4代41名成员中有11名被临床确诊为HHT，其中先证者及其2个女儿均合并多脏器损害，小女儿仅有影像学表现而无相应临床症状。母女3人的PCR产物序列分析显示，ALK-1基因的9号外显子cDNA上第1 321位均发生错义突变(c.1321G>A)，该突变导致ALK-1蛋白441位缬氨酸变为蛋氨酸(p.Va1441Met)。
结论: 报告了1个HHT家系，并发现该家系中ALK-1基因发生错义突变(c.1321G> A, p.Va1441Met）。该突变是这个家系致病的遗传学基础。