Mutations within the MGC4607 gene cause cerebral cavernous malformations
Mutations within the MGC4607 gene cause cerebral cavernous malformations
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DOI：
10.1086/381718
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发表时间：
2004-02-01
影响因子：
9.8
通讯作者：
Tournier-Lasserve, E
中科院分区：
文献类型：
--
作者：
Denier, C;Goutagny, S;Tournier-Lasserve, E
脑海绵状血管畸形（CCM）是一种以毛细血管腔异常扩大为特征的血管畸形，无脑实质介入。它们会引起癫痫发作和由于脑损伤引起的局灶性神经功能缺损。CCM基因座已经被分配到染色体7 q（CCM 1）、7 p（CCM 2）和3q（CCM 3），并且已经分别在40%、20%和40%的CCM家族中被鉴定。已在CCM 1/KRIT 1中鉴定出功能丧失突变，这是迄今为止鉴定出的唯一CCM基因。我们在这里报告的鉴定MGC 4607的CCM 2基因。我们首先通过遗传连锁分析将CCM 2区间的大小从22 cM减小到7.5 cM。然后我们假设，大的缺失可能参与了这种疾病，正如已经报道的其他错构瘤疾病，如结节性硬化症或神经纤维瘤病。我们进行了高密度的微卫星基因分型，这7.5 cM的间隔，以寻找假定的无效等位基因在30个无关的家庭，我们确定，在2个无关的家庭，无效等位基因，这是由两侧标记D 7S 478和D 7S 621的350 kb的间隔内的缺失的结果。额外的微卫星和单核苷酸多态性基因分型表明，这两个不同的缺失重叠，这两个删除MGC 4607，一个未知功能的已知基因的第一个外显子。在两个家系中，两个MGC 4607转录本中的一个未检测到。然后，我们在剩下的8个家族中确定了MGC 4607内的8个额外的点突变。其中一个导致起始密码子的改变，其中五个导致提前终止密码子的改变，包括一个无义突变、一个移码突变和三个剪接位点突变。所有这些突变在家系中与疾病共分离，在192条对照染色体中未观察到。MGC 4607与任何已知的基因家族无关。它在CCM中的意义强烈表明它是血管形态发生中的新参与者。
Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3) and have been identified in 40%, 20%, and 40%, respectively, of families with CCM. Loss-of-function mutations have been identified in CCM1/KRIT1, the sole CCM gene identified to date. We report here the identification of MGC4607 as the CCM2 gene. We first reduced the size of the CCM2 interval from 22 cM to 7.5 cM by genetic linkage analysis. We then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions, such as tuberous sclerosis or neurofibromatosis. We performed a high-density microsatellite genotyping of this 7.5-cM interval to search for putative null alleles in 30 unrelated families, and we identified, in 2 unrelated families, null alleles that were the result of deletions within a 350-kb interval flanked by markers D7S478 and D7S621. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these two distinct deletions overlapped and that both of the two deleted the first exon of MGC4607, a known gene of unknown function. In both families, one of the two MGC4607 transcripts was not detected. We then identified eight additional point mutations within MGC4607 in eight of the remaining families. One of them led to the alteration of the initiation codon and five of them to a premature termination codon, including one nonsense, one frameshift, and three splice-site mutations. All these mutations cosegregated with the disease in the families and were not observed in 192 control chromosomes. MGC4607 is so far unrelated to any known gene family. Its implication in CCMs strongly suggests that it is a new player in vascular morphogenesis.