GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier
GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier
复制标题
DOI：
10.1038/ng0298-188
复制
发表时间：
1998-02-01
期刊：
影响因子：
30.8
通讯作者：
De Vivo, DC
中科院分区：
文献类型：
--
作者：
Seidner, G;Alvarez, MG;De Vivo, DC
哺乳动物中枢神经系统的高代谢需求需要专门的结构来促进营养物质穿过血脑屏障的运输。立体特异性高容量载体，包括那些识别葡萄糖的载体，是这种屏障的关键组成部分，它也保护大脑免受有害物质的侵害。脊椎动物中的葡萄糖促进转运由一个载体家族催化，该家族由至少五种具有不同组织分布、亚细胞定位和转运动力学的功能同种型组成（1，2）。其中几种转运蛋白在哺乳动物大脑中表达（3）。GLUT-1的序列最初是从人肝癌和大鼠脑克隆的cDNA推导出来的（4，5），在灵长类动物红细胞和脑内皮细胞中以高水平存在。GLUT 1已被克隆并定位于1号染色体的短臂（1 p35-p31.3;参考文献6-8）。尽管中枢神经系统有大量的代谢需求，但尚未发现由血脑屏障转运功能障碍引起的遗传疾病。几年前，我们描述了2例婴儿癫痫发作、发育延迟和获得性小头畸形的患者，他们循环血糖正常，脑脊液（CSF）乳酸低至正常，但持续性低血糖（CSF葡萄糖低）和己糖转运至分离红细胞（RBC;参考文献9）减少。这些症状表明存在葡萄糖转运通过血脑屏障的缺陷。我们现在报告两类不同的突变作为葡萄糖转运功能缺陷的分子基础：GLUT 1的半合子和无义突变导致GLUT-1蛋白的截短。
The high metabolic requirements of the mammalian central nervous system require specialized structures for the facilitated transport of nutrients across the blood-brain barrier. Stereospecific high-capacity carriers, including those that recognize glucose, are key components of this barrier, which also protects the brain against noxious substances. Facilitated glucose transport in vertebrates is catalyzed by a family of carriers consisting of at least five functional isoforms with distinct tissue distributions, subcellular localizations and transport kinetics(1,2). Several of these transporters are expressed in the mammalian brain(3). GLUT-1, whose sequence was originally deduced from cDNAs cloned from human hepatoma and rat brain(4,5), is present at high levels in primate erythrocytes and brain endothelial cells. GLUT1 has been cloned and positionally mapped to the short arm of chromosome 1 (1p35-p31.3; refs 6-8). Despite substantial metabolic requirements of the central nervous system, no genetic disease caused by dysfunctional blood-brain barrier transport has been identified. Several years ago, we described two patients with infantile seizures, delayed development and acquired microcephaly who have normal circulating blood glucose, low-to-normal cerebrospinal fluid (CSF) lactate, but persistent hypoglycorrachia (low CSF glucose) and diminished transport of hexose into isolated red blood cells (RBC; ref. 9). These symptoms suggested the existence of a defect in glucose transport across the blood brain barrier. We now report two distinct classes of mutations as the molecular basis for the functional defect of glucose transport: hemizygosity of GLUT1 and nonsense mutations resulting in truncation of the GLUT-1 protein.