Somatic second hit mutation of RASA1 in vascular endothelial cells in capillary malformation-arteriovenous malformation.
Somatic second hit mutation of RASA1 in vascular endothelial cells in capillary malformation-arteriovenous malformation.
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DOI：
10.1016/j.ejmg.2017.10.004
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发表时间：
2018-01
影响因子：
1.9
通讯作者：
King PD
中科院分区：
文献类型：
--
作者：
Lapinski PE;Doosti A;Salato V;North P;Burrows PE;King PD
毛细血管畸形-动静脉畸形(CM-AVM)是一种常染色体显性遗传性血管疾病，在大多数病例中与RASA1基因的遗传失活突变有关。特征性的是，患者表现出一个或多个局灶性皮肤CM，可单独或与AVM、动静脉瘘或淋巴管异常一起发生。病变的局灶性和不同的表现形式导致了这样的假说，即躯体“二次打击”RASA1的失活突变是疾病发展所必需的。在这项研究中，我们检查了来自四个不同CM-AVM患者的CM是否存在躯体获得性RASA1突变。所有四名患者都具有失活的杂合子种系RASA1突变。在其中一例患者中，在CM病变组织中还发现了一个体细胞失活RASA1突变(c.1534C>；T，p.Arg512*)。体细胞RASA1突变特异性地存在于内皮细胞中，并且与种系RASA1突变是反式的。与同一患者的种系RASA1突变(c.2125C>；T，p.Arg709*)一起，内皮细胞体细胞RASA1突变可能与病变的发生有关。这些研究首次为CM-AVM发病机制的第二次HIT模型提供了明确的证据。
Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant vascular disorder that is associated with inherited inactivating mutations of the RASA1 gene in the majority of cases. Characteristically, patients exhibit one or more focal cutaneous CM that may occur alone or together with AVM, arteriovenous fistulas or lymphatic vessel abnormalities. The focal nature and varying presentation of lesions has led to the hypothesis that somatic “second hit” inactivating mutations of RASA1 are necessary for disease development. In this study, we examined CM from four different CM-AVM patients for the presence of somatically acquired RASA1 mutations. All four patients were shown to possess inactivating heterozygous germline RASA1 mutations. In one of the patients, a somatic inactivating RASA1 mutation (c.1534C>T, p.Arg512*) was additionally identified in CM lesion tissue. The somatic RASA1 mutation was detected within endothelial cells specifically and was in trans with the germline RASA1 mutation. Together with the germline RASA1 mutation (c.2125C>T, p.Arg709*) in the same patient, the endothelial cell somatic RASA1 mutation likely contributed to lesion development. These studies provide the first clear evidence of the second hit model of CM-AVM pathogenesis.
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影响因子：
7.3
作者：
King PD;Lubeck BA;Lapinski PE
通讯作者：
Lapinski PE
影响因子：
2.6
作者：
Cho, Sung Ki;Do, Young Soo;Choo, In-Wook
通讯作者：
Choo, In-Wook
影响因子：
3.9
作者：
Revencu, Nicole;Boon, Laurence M.;Vikkula, Miikka
通讯作者：
Vikkula, Miikka
影响因子：
64.8
作者：
HENKEMEYER, M;ROSSI, DJ;PAWSON, T
通讯作者：
PAWSON, T
影响因子：
6
作者：
Lubeck, Beth A.;Lapinski, Philip E.;King, Philip D.
通讯作者：
King, Philip D.