Eerola I, Plate K H, Spiegel R, Boon L M, Mulliken J B, Vikkula M
Laboratory of Human Molecular Genetics, Institute of Cellular Pathology (ICP) and Université Catholique de Louvain (UCL), Avenue Hippocrate 75+4, B-1200 Brussels, Belgium,
Hum Mol Genet. 2000 May 22;9(9):1351-5. doi: 10.1093/hmg/9.9.1351.
Hyperkeratotic capillary-venous malformations (HCCVMs) are rare cutaneous lesions that occur in a small subgroup of patients with cerebral capillary malformation (CCM). CCMs cause neurological problems that range from headaches to life-threatening intracranial bleeding. CCMs and HCCVMs have a similar histopathological appearance of dilated capillary-venous channels. Genetic linkage of inherited CCMs has been established to three chromosomal loci, 3q25. 2-27, 7p13-15 and 7q21-22. The first mutations were identified in the CCM1 gene (located on 7q21-22), which encodes KRIT1 protein (KREV1 interaction trapped 1), presumably a membrane-bound protein with signalling activity. Although KRIT1 is known to interact with KREV1/RAP1A, a Ras-family GTPase, the exact function of KRIT1 in the formation of cerebral capillaries and veins is poorly understood. In this study, we screened five families with CCM for mutations in the KRIT1 gene. In one of the families, CCMs co-segregated with HCCVMs. We identified a KRIT1Delta(G103)mutation in this family, suggesting that this rare form of the condition is also caused by mutations in the CCM1 gene and that KRIT1 is probably important for cutaneous vasculature. Interestingly, this deletion introduces the earliest stop codon among identified mutations, suggesting a possible correlation between the molecular alteration and the cutaneous phenotype. Another novel mutation, KRIT1(IVS2+2(T-->C)), was found in a family with only cerebral capillary-venous malformations.
角化过度性毛细血管-静脉畸形（HCCVMs）是一种罕见的皮肤病变，发生于一小部分患有脑毛细血管畸形（CCM）的患者中。CCM会引发从头痛到危及生命的颅内出血等一系列神经问题。CCM和HCCVMs在组织病理学上具有相似的扩张性毛细血管-静脉通道表现。遗传性CCM的基因连锁已确定位于三个染色体位点，即3q25.2 - 27、7p13 - 15和7q21 - 22。最初的突变在CCM1基因（位于7q21 - 22）中被发现，该基因编码KRIT1蛋白（KREV1相互作用捕获蛋白1），推测是一种具有信号传导活性的膜结合蛋白。尽管已知KRIT1与Ras家族GTP酶KREV1/RAP1A相互作用，但KRIT1在脑毛细血管和静脉形成中的具体功能仍知之甚少。在本研究中，我们对五个患有CCM的家族进行了KRIT1基因突变筛查。在其中一个家族中，CCM与HCCVMs共分离。我们在这个家族中鉴定出一个KRIT1Delta(G103)突变，这表明这种罕见形式的病症也是由CCM1基因突变引起的，并且KRIT1可能对皮肤血管系统很重要。有趣的是，这种缺失在已鉴定的突变中引入了最早的终止密码子，提示分子改变与皮肤表型之间可能存在关联。在另一个仅患有脑毛细血管-静脉畸形的家族中发现了另一个新的突变KRIT1(IVS2 + 2(T→C))。
