LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation
LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation
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DOI：
10.1093/hmg/7.13.2029
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发表时间：
1998-12-01
影响因子：
3.5
通讯作者：
Ross, ME
中科院分区：
文献类型：
--
作者：
Pilz, DT;Matsumoto, N;Ross, ME
典型无脑畸形（LIS）是一种神经元迁移障碍，可导致脑畸形、癫痫和智力低下。17p13.3的LIS 1缺失或突变以及Xq22.3-q23的XLIS突变（DCX）均产生LIS。应用荧光原位杂交技术对25例散发性LIS患儿的LIS 1和XLIS进行了DNA直接测序。测序（n = 8）和Southern印迹（n = 2）发现10例（40%）男性和10例（20%）男性患者存在LIS 1突变，结合既往资料，这两个基因的缺失或突变占分离LIS的76%。这些数据表明，LIS 1和XLIS突变导致大多数，但不是全部，人LIS。预测LIS 1中的突变导致8名患者中的6名的蛋白质截短和2名的剪接位点突变，所有这些都破坏了LIS 1蛋白中包含的7个WD 40重复序列中的一个或多个。XLIS中的点突变确定了C-末端丝氨酸/脯氨酸丰富的区域对蛋白质功能具有潜在的重要性。突变的患者包括在32例这两个基因缺失或其他突变的受试者的基因型-表型分析中。然而，由于LIS 1突变导致的脑畸形在顶叶和枕叶区域更严重，XLIS突变产生了相反的梯度，在额叶皮层更严重。不同的LIS模式表明，LIS 1和XLIS可能是重叠的，但不同的，促进神经元迁移的信号通路的一部分。
Classical lissencephaly (LIS) is a neuronal migration disorder resulting in brain malformation, epilepsy and mental retardation. Deletions or mutations of LIS1 on 17p13.3 and mutations in XLIS (DCX) on Xq22.3-q23 produce LIS, Direct DNA sequencing of: LIS1 and XLIS was performed in 25 children with sporadic LIS and no deletion of LIS1 by fluorescence in situ hybridization. Mutations of LIS1 were found by sequencing (n = 8) and Southern blot (n = 2) in a total of 10 patients (40%) of both sexes and mutations of XLIS in five males (20%), Combined with previous data, deletions or mutations of these two genes account for similar to 76% of isolated LIS. These data demonstrate that LIS1 and XLIS mutations cause the majority of, though not all, human LIS, The mutations in LIS1 were predicted to result in protein truncation in six of eight patients and splice site mutations in two, all of which disrupt one or more of the seven WD40 repeats contained in the LIS1 protein. Point mutations in XLIS identified the C-terminal serine/proline-rich region as potentially important for protein function. The patients with mutations were included in a genotype-phenotype analysis of 32 subjects with deletions or other mutations of these two genes. Whereas the brain malformation due to LIS1 mutations was more severe over the parietal and occipital regions, XLIS mutations produced the reverse gradient, which was more severe over the frontal cortex. The distinct LIS patterns suggest that LIS1 and XLIS may be part of overlapping, but distinct, signaling pathways that promote neuronal migration.