Comasco Erika, Vumma Ravi, Toffoletto Simone, Johansson Jessica, Flyckt Lena, Lewander Tommy, Oreland Lars, Bjerkenstedt Lars, Andreou Dimitrios, Söderman Erik, Terenius Lars, Agartz Ingrid, Jönsson Erik G, Venizelos Nikolaos
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Neuropsychobiology. 2016;74(2):96-103. doi: 10.1159/000455234. Epub 2017 Feb 11.
Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the L-type amino acid transporter 1 (LAT1). The present study assessed haplotype tag single-nucleotide polymorphisms (SNPs) of the SLC7A5/LAT1 gene in 315 patients with psychosis within the schizophrenia spectrum and 233 healthy controls to investigate genetic vulnerability to the disorder as well as genetic relationships to homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major catecholamine metabolites in the cerebrospinal fluid (CSF). Moreover, the involvement of the different isoforms of the system L in tyrosine uptake and LAT1 tyrosine kinetics were studied in fibroblast cell lines of 10 patients with schizophrenia and 10 healthy controls. The results provide suggestive evidence of individual vulnerability to schizophrenia related to the LAT1 SNP rs9936204 genotype. A number of SNPs were nominally associated with CSF HVA and MHPG concentrations but did not survive correction for multiple testing. The LAT1 isoform was confirmed as the major tyrosine transporter in patients with schizophrenia. However, the kinetic parameters (maximal transport capacity, affinity of the binding sites, and diffusion constant of tyrosine transport through the LAT1 isoform) did not differ between patients with schizophrenia and controls. The present genetic findings call for independent replication in larger samples, while the functional study seems to exclude a role of LAT1 in the aberrant transport of tyrosine in fibroblasts of patients with schizophrenia.
精神分裂症涉及神经儿茶酚胺能调节异常。酪氨酸是儿茶酚胺的前体，根据对成纤维细胞的研究，其在大脑中的主要转运体是L型氨基酸转运体1（LAT1）。本研究评估了315例精神分裂症谱系内精神病患者和233名健康对照者中SLC7A5/LAT1基因的单倍型标签单核苷酸多态性（SNP），以研究该疾病的遗传易感性以及与脑脊液（CSF）中主要儿茶酚胺代谢产物高香草酸（HVA）和3-甲氧基-4-羟基苯乙二醇（MHPG）的遗传关系。此外，在10例精神分裂症患者和10名健康对照者的成纤维细胞系中研究了L系统不同亚型在酪氨酸摄取中的作用以及LAT1酪氨酸动力学。结果提供了与LAT1 SNP rs9936204基因型相关的个体对精神分裂症易感性的提示性证据。一些SNP与CSF中HVA和MHPG浓度名义上相关，但在多重检验校正后未通过。LAT1亚型被确认为精神分裂症患者中主要的酪氨酸转运体。然而，精神分裂症患者和对照者之间的动力学参数（最大转运能力、结合位点亲和力以及酪氨酸通过LAT1亚型的扩散常数）并无差异。目前的遗传研究结果需要在更大样本中进行独立验证，而功能研究似乎排除了LAT1在精神分裂症患者成纤维细胞中酪氨酸异常转运中的作用。
