Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts
Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts
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DOI：
10.1086/319519
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发表时间：
2001-04-01
影响因子：
9.8
通讯作者：
van der Knaap, MS
中科院分区：
文献类型：
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作者：
Leegwater, PAJ;Yuan, BQ;van der Knaap, MS
巨脑白质脑病合并皮质下囊肿(MLC)是一种常染色体隐性遗传病，以大头畸形、运动功能减退、共济失调和痉挛为特征，最终导致智力下降。磁共振成像显示大脑肿胀，弥漫性白质异常，皮质下囊肿不变。MLC最近被定位在染色体22q(Tel)上。我们通过对11个MLC信息性家系的连锁分析，缩小了关键区域的范围，得到了一个类似于250kb的区域，其中包含4个已知基因。一个有两个兄弟姐妹的家庭没有显示出MLC表型与染色体22q(Tel)上任何分析的微卫星标记之间的关联，这表明存在遗传异质性和至少第二个MLC基因座的存在。在重组分数为0.02时，11个家系的最大两点LOD得分为6.6。在一个候选基因KIAA0027中，我们发现了7个信息性和6个非信息性家族的12个不同的突变，我们将其重新命名为“MLC1”。该基因编码一个假定的膜蛋白，具有8个预测的跨膜结构域。一个家族的患者是两个都引入终止密码子的突变的复合杂合子。这些突变还包括移码、剪接-受体突变、假定的剪接-供体突变以及预测跨膜区残基的氨基酸替换。这些数据提供了MLC1突变导致这种疾病的有力证据。
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive disorder characterized by macrocephaly, deterioration of motor functions with ataxia, and spasticity, eventuating in mental decline. The brain appears swollen on magnetic resonance imaging, with diffuse white-matter abnormalities and the invariable presence of subcortical cysts. MLC was recently localized on chromosome 22q(tel). We have narrowed down the critical region by linkage analysis of 11 informative families with MLC to a region of similar to 250 kb, containing four known genes. One family with two patients who were siblings did not display linkage between the MLC phenotype and any of the analyzed microsatellite markers on chromosome 22q(tel), suggesting genetic heterogeneity and the existence of at least a second MLC locus. The maximum two-point LOD score for the 11 families was 6.6 at recombination fraction .02. Twelve different mutations in seven informative and six uninformative families were found in one of the candidate genes, KIAA0027, which we renamed "MLC1." The gene encodes a putative membrane protein with eight predicted transmembrane domains. The patients of one family were compound heterozygotes for mutations that both introduced stop codons. The mutations further included frameshifts, splice-acceptor mutations, a putative splice-donor mutation, and amino acid substitutions of residues in predicted transmembrane domains. These data provide strong evidence that mutations of MLC1 cause the disease.