Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations
Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations
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DOI：
10.1086/379793
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发表时间：
2003-12-01
影响因子：
9.8
通讯作者：
Vikkula, M
中科院分区：
文献类型：
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作者：
Eerola, I;Boon, LM;Vikkula, M
毛细血管畸形（CM）或“葡萄酒色斑”是一种常见的皮肤血管异常，最初表现为红色黄斑色斑，多年后变暗。CM也发生在几种表现出肥大的联合血管异常中，如Sturge-Weber综合征、Klippel-Trenaunay综合征和Parkes Weber综合征。偶尔的CM家族分离表明，有遗传易感性，强调了一个大的基因座，CMC 1，染色体5 q上的鉴定。我们使用遗传精细定位与多态性标记，以减少CMC 1位点的大小。一个位置候选基因，RASA 1，编码p120-RasGAP，筛选突变的17个家庭。杂合失活RASA 1突变在6个家族中检测到，表现为多个、小、圆形至椭圆形、粉红色的非典型CM。除CM外，所有突变家族中均记录有动静脉畸形、动静脉瘘或Parkes Weber综合征。我们将这种新发现的由RASA 1突变引起的相关性命名为“CM-AVM”，即毛细血管畸形-动静脉畸形。表型变异性可以通过p120-RasGAP参与控制包括血管内皮细胞在内的几种细胞类型的增殖、迁移和存活的各种生长因子受体的信号传导来解释。
Capillary malformation (CM), or "port-wine stain," is a common cutaneous vascular anomaly that initially appears as a red macular stain that darkens over years. CM also occurs in several combined vascular anomalies that exhibit hypertrophy, such as Sturge-Weber syndrome, Klippel-Trenaunay syndrome, and Parkes Weber syndrome. Occasional familial segregation of CM suggests that there is genetic susceptibility, underscored by the identification of a large locus, CMC1, on chromosome 5q. We used genetic fine mapping with polymorphic markers to reduce the, size of the CMC1 locus. A positional candidate gene, RASA1, encoding p120-RasGAP, was screened for mutations in 17 families. Heterozygous inactivating RASA1 mutations were detected in six families manifesting atypical CMs that were multiple, small, round to oval in shape, and pinkish red in color. In addition to CM, either arteriovenous malformation, arteriovenous fistula, or Parkes Weber syndrome was documented in all the families with a mutation. We named this newly identified association caused by RASA1 mutations "CM-AVM," for capillary malformation-arteriovenous malformation. The phenotypic variability can be explained by the involvement of p120-RasGAP in signaling for various growth factor receptors that control proliferation, migration, and survival of several cell types, including vascular endothelial cells.