title: Genetic and Functional Study of L-Type Amino Acid Transporter 1 in Schizophrenia.
abstract: 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.
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Erika
authors.initials: E
authors.lastname: Comasco
authors.forename: Ravi
authors.initials: R
authors.lastname: Vumma
authors.forename: Simone
authors.initials: S
authors.lastname: Toffoletto
authors.forename: Jessica
authors.initials: J
authors.lastname: Johansson
authors.forename: Lena
authors.initials: L
authors.lastname: Flyckt
authors.forename: Tommy
authors.initials: T
authors.lastname: Lewander
authors.forename: Lars
authors.initials: L
authors.lastname: Oreland
authors.forename: Lars
authors.initials: L
authors.lastname: Bjerkenstedt
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Andreou
authors.forename: Erik
authors.initials: E
authors.lastname: Söderman
authors.forename: Lars
authors.initials: L
authors.lastname: Terenius
authors.forename: Ingrid
authors.initials: I
authors.lastname: Agartz
authors.forename: Erik G
authors.initials: EG
authors.lastname: Jönsson
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Venizelos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000134:cerebrospinal fluid; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D055815:Young Adult
chemical_list: D027283:Large Neutral Amino Acid-Transporter 1; D020033:Protein Isoforms; D014443:Tyrosine; D008734:Methoxyhydroxyphenylglycol; D006719:Homovanillic Acid