KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation
KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation
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DOI：
10.1093/hmg/9.9.1351
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发表时间：
2000-05-22
影响因子：
3.5
通讯作者：
Vikkula, M
中科院分区：
文献类型：
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作者：
Eerola, I;Plate, KH;Vikkula, M
角化性毛细血管-静脉畸形（hccvm）是一种罕见的皮肤病变，发生在一小部分脑毛细血管畸形（CCM）患者中。CCMs引起从头痛到危及生命的颅内出血的神经系统问题，CCMs和hccvm具有相似的毛细血管-静脉通道扩张的组织病理学表现。遗传性CCMs与3q25.2-27、7p13-15和7q21-22三个染色体位点建立了遗传连锁。第一个突变是在CCM1基因（位于7q21-22）中发现的，该基因编码KRIT1蛋白（KREV1相互作用捕获1），可能是一种具有信号活性的膜结合蛋白。虽然已知KRIT1与ras家族GTPase KREV1/RAP1A相互作用，但KRIT1在脑毛细血管和静脉形成中的确切功能尚不清楚。在本研究中，我们筛选了5个CCM家族的KRIT1基因突变。在其中一个家庭中，ccm与hccvm共同隔离。我们在这个家族中发现了一个KRIT1 Delta（G103）突变，这表明这种罕见的疾病也是由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，这种缺失在已确定的突变中引入了最早的停止密码子，这表明分子改变与皮肤表型之间可能存在关联。另一种新的突变，KRIT1(IVS2+2(T- >C))，在一个只有脑毛细静脉畸形的家庭中被发现。
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 KRIT1 Delta(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.