Lapinski Philip E, Doosti Abbas, Salato Valerie, North Paula, Burrows Patricia E, King Philip D
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48103, USA.
Department of Pathology, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
Eur J Med Genet. 2018 Jan;61(1):11-16. doi: 10.1016/j.ejmg.2017.10.004. Epub 2017 Oct 9.
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.
毛细血管畸形 - 动静脉畸形（CM - AVM）是一种常染色体显性血管疾病，在大多数情况下与RASA1基因的遗传性失活突变相关。典型的是，患者表现出一个或多个局灶性皮肤CM，其可单独出现或与AVM、动静脉瘘或淋巴管异常一起出现。病变的局灶性性质和不同表现导致了这样一种假说，即RASA1的体细胞“二次打击”失活突变对于疾病发展是必要的。在本研究中，我们检查了四名不同CM - AVM患者的CM，以寻找体细胞获得性RASA1突变的存在。所有四名患者均显示具有失活的杂合种系RASA1突变。在其中一名患者中，在CM病变组织中另外鉴定出一个体细胞失活RASA1突变（c.1534C>T，p.Arg512*）。体细胞RASA1突变特异性地在内皮细胞中检测到，并且与种系RASA1突变呈反式。与同一名患者中的种系RASA1突变（c.2125C>T，p.Arg709*）一起，内皮细胞体细胞RASA1突变可能促成了病变发展。这些研究为CM - AVM发病机制的二次打击模型提供了首个明确证据。
