Defective SLC1A1 is implicated in schizophrenia 18 (SCZD18) and dicarboxylic aminoaciduria (DCBXA)

There are two classes of glutamate transporters; the excitatory amino acid transporters (EAATs) which depend on an electrochemical gradient of Na+ ions and vesicular glutamate transporters (VGLUTs) which are proton-dependent. Together, these transporters uptake and release glutamate to mediate this neurotransmitter's excitatory signal and are part of the glutamate-glutamine cycle.<br><br>The SLC1 gene family includes five high-affinity glutamate transporters encoded by SLC1, 2, 3, 6 and 7. These transporters can mediate transport of L-Glutamate (L-Glu), L-Aspartate (L-Asp) and D-Aspartate (D-Asp) with cotransport of 3 Na+ ions and H+ and antiport of a K+ ion. This mechanism allows glutamate into cells against a concentration gradient. This is a crucial factor in the protection of neurons against glutamate excitotoxicity (the excitation of nerve cells to their death) in the CNS (Zhou & Danbolt 2014).<br><br>SLC1A1 encodes an excitatory amino-acid carrier 1 (EAAC1, also called EAAT3) and is abundant particularly in brain but also in kidney, liver, muscle, ovary, testis and in retinoblastoma cell lines. In the kidney, SLC1A1 is present at apical membranes of proximal tubes where it serves as a major route of glutamate and aspartate reuptake from urine. Defects in SLC1A1 are the cause of dicarboxylic aminoaciduria (DCBXA; MIM:222730), an autosomal recessive glutamate-aspartate transport defect in the kidney and intestine (Bailey et al. 2011). Mutations that can cause DCBXA are R445W and I395del (Bailey et al. 2011).<br><br>A defect in SLC1A1 is also implicated in schizophrenia 18 (SCZD18; MIM:615232). Schizophrenia (SCZD; MIM:181500) is a complex, multifactorial psychotic disorder characterised by disturbances in the form and content of thought, in mood, in sense of self and relationship to the external world and in behaviour. It ranks amongst the world's top 10 causes of long-term disability. At the neuropathological level, SCZD appears to be characterised by synaptic deficits, alterations in glutamate and dopamine neurotransmission and hypofrontality (a state of decreased cerebral blood flow (CBF) in the prefrontal cortex of the brain). Variations in the SLC1A1 gene can confer susceptibility to SCZD18 (Harris et al. 2013). In the remote Pacific island of Palau, the risk of SCZD is 2-3 times the worldwide rate. In a 5-generation Palauan family, an 84kb deletion was carried by psychosis patients and proposed to increase the disease risk more than 18-fold for family members (Myles-Worsley et al. 2013).

谷氨酸转运蛋白可分为两大类：一类为兴奋性氨基酸转运蛋白（EAATs），其转运依赖于钠离子（Na+）的电化学梯度；另一类为囊泡型谷氨酸转运蛋白（VGLUTs），其转运则依赖于质子。这些转运蛋白共同参与谷氨酸的摄取与释放，以介导该神经递质的兴奋性信号，并构成谷氨酸-谷氨酰胺循环的重要组成部分。<br><br>SLC1基因家族包括由SLC1、2、3、6和7编码的五种高亲和力谷氨酸转运蛋白。这些转运蛋白能够介导L-谷氨酸（L-Glu）、L-天冬氨酸（L-Asp）和D-天冬氨酸（D-Asp）的转运，并伴随3个钠离子（Na+）和氢离子（H+）的共转运，以及钾离子（K+）的反向转运。此机制使得谷氨酸得以逆浓度梯度进入细胞，这是在中枢神经系统（CNS）中保护神经元免受谷氨酸兴奋性毒性（神经细胞过度兴奋导致死亡）的关键因素（Zhou & Danbolt 2014）。<br><br>SLC1A1基因编码兴奋性氨基酸载体1（EAAC1，亦称EAAT3），在脑中尤为丰富，亦见于肾脏、肝脏、肌肉、卵巢、睾丸及视网膜母细胞瘤细胞系。在肾脏中，SLC1A1位于近端小管的顶端膜上，是谷氨酸和天冬氨酸从尿液重新摄取的主要途径。SLC1A1基因的缺陷是导致二羧基氨基酸尿症（DCBXA；MIM:222730）的原因，这是一种常染色体隐性遗传的肾脏和肠道谷氨酸-天冬氨酸转运缺陷（Bailey et al. 2011）。可导致DCBXA的突变包括R445W和I395del（Bailey et al. 2011）。<br><br>SLC1A1基因的缺陷还与精神分裂症18（SCZD18；MIM:615232）有关。精神分裂症（SCZD；MIM:181500）是一种复杂的、多因素的精神分裂性疾病，其特征为思维形式和内容、情绪、自我意识及与外部世界的关系以及行为的紊乱。它是全球导致长期残疾的前十大原因之一。在神经病理学层面上，精神分裂症似乎以突触缺陷、谷氨酸和多巴胺神经传递的改变以及前额叶皮层血流减少（CBF降低）为特征。SLC1A1基因的变异可增加SCZD18的易感性（Harris et al. 2013）。在遥远的太平洋岛屿帕劳，精神分裂症的风险是全球平均水平的2-3倍。在一个五代帕劳家庭中，精神病患者携带了一个84kb的缺失，该缺失被提议能将家庭成员的疾病风险增加18倍以上（Myles-Worsley et al. 2013）。