ACVRL1 gene variant in a patient with vein of Galen aneurysmal malformation
ACVRL1 gene variant in a patient with vein of Galen aneurysmal malformation
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DOI：
10.3233/pge-13067
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发表时间：
2013-12-01
影响因子：
0.4
通讯作者：
Nakanishi, Toshio
中科院分区：
文献类型：
--
作者：
Chida, Ayako;Shintani, Masaki;Nakanishi, Toshio
虽然已在有遗传性出血性毛细血管扩张症(HHT)家族史的Galen静脉动脉瘤样畸形(VGAM)患者中发现RASA1基因突变和endoglin基因突变，但大多数VGAM患者均未发现这些基因突变。我们试图检测与HHT相关的其他基因的突变。我们筛查了4例VGAM患者RASA1和三个与HHT相关的基因(endoglin、激活素受体样激酶1(ACVRL1)，编码ALK1和Smad4)的突变。在ACVRL1中发现了一个变异(c.652 C>；T p.R218W)。免疫印迹显示，ALK1-R218W蛋白不能通过BMP9刺激促进Smad1/5/8的磷酸化。另一方面，野生型ALK1可以像预期的那样增强磷酸化。此外，ALK1-R218W的转录激活效率低于野生型ALK1。我们在1例VGAM患者中发现了ACVRL1的1个变异体。这些发现提示ACVRL1变异-R218W可能与VGAM的发病有关。
Although mutations in the RASA1 gene in vein of Galen aneurysmal malformation (VGAM) and an endoglin gene mutation in a VGAM patient with a family history of hereditary hemorrhagic telangiectasia (HHT) have been identified, most VGAM cases have no mutation in these genes. We sought to detect mutations in other genes related to HHT. We screened for mutations in RASA1 and three genes (endoglin, activin receptor-like kinase 1 (ACVRL1), encoding ALK1, and SMAD4) related to HHT in four VGAM patients. One variant (c.652 C>T p.R218W) in ACVRL1 was identified. Immunoblotting revealed that the ALK1-R218W protein could not promote SMAD1/5/8 phosphorylation by BMP9 stimulation. On the other hand, wild-type ALK1 could enhance the phosphorylation as expected. Furthermore, the transcriptional activation of ALK1-R218W was less efficient than that of wild-type ALK1. We identified 1 variant in ACVRL1 in a VGAM patient. These findings suggest that the ACVRL1 variant-R218W may be associated with the pathogenesis of VGAM.