A novel balanced chromosomal translocation found in subjects with schizophrenia and schizotypal personality disorder: Altered l-serine level associated with disruption of PSAT1 gene expression

Abstract

L-Serine is required for the synthesis of glycine and D-serine, both of which are NMDA receptor co-agonists. Although roles for D-serine and glycine have been suggested in schizophrenia, little is known about the role of the L-serine synthesizing cascade in schizophrenia or related psychiatric conditions. Here we report a patient with schizophrenia carrying a balanced chromosomal translocation with the breakpoints localized to 3q13.12 and 9q21.2. We examined this proband and her son with schizotypal personality disorder for chromosomal abnormalities, molecular expression profiles, and serum amino acids. Marked decrease of L-serine and glutamate was observed in the sera of the patient and her son, compared with those in normal controls. Interestingly, expression of PSAT1 gene, which is located next to the breakpoint and encodes one of the enzymes in the L-serine synthesizing cascade, was reduced in both patient and her son. Direct effect of impaired PSAT1 gene expression on decreased serum L-serine level was strongly implicated by rat astrocyte experiments. In summary, we propose an idea that PSAT1 may be implicated in altered serine metabolism and schizophrenia spectrum conditions.

Analysis of Gene Expression Variance in Schizophrenia Using Structural Equation Modeling

“…Mutations in PSAT1 , which regulates PSPH , affect neurodevelopment (Tabatabaie et al, 2010). There is also evidence that the gene is implicated in SCZ based on a study of gene expression in a family with a chromosomal translocation near PSAT1 associated with SCZ and schizotypal personality disorder (Ozekia et al, 2012). The second gene in the interaction, SHMT2 , demonstrated the overexpression and regulatory function (suppression and promotion) in migration and proliferation in carcinoma cells (Wu et al, 2016).…”

Hepatic Phosphoserine Aminotransferase 1 Regulates Insulin Sensitivity in Mice via Tribbles Homolog 3

“…PSAT1 is an enzyme that participates in serine synthesis pathway and increases serine levels (19), suggesting that PSAT1 might regulate TRB3 expression via altered serine levels. Although serum serine levels remained unchanged, liver serine levels were significantly increased in Ad-PSAT1 mice and decreased in Ad-shPSAT1 mice compared with their respective control mice (Fig.…”

“…Three steps are involved in serine synthesis (11), and PSAT1 is involved in the second step catalyzing the 3-phosphohydroxypyruvate to form L-phosphoserine (11,12). Serine contributes to the regulation of several physiological processes (13)(14)(15)(16), and, as one of a key enzymes in serine synthesis, PSAT1 has some important metabolic functions (17)(18)(19). For example, PSAT1 deficiency results in intractable seizures and acquired microcephaly (17), while increased expression of PSAT1 is associated with the development of colorectal cancer (18).…”

“…For example, PSAT1 regulates serine synthesis (19), and serine reportedly regulates glycogen synthesis (16). In addition, a-ketoglutaric acid, as a by-product of PSAT1 catalyzed reaction (14), stimulates insulin secretion (20).…”

Increased Tyrosine in the Brain and Serum of Mice by Orally Administering Dipeptide SY

“…A recent study has reported that a family with schizophrenia had a chromosomal translocation, which reduced the expression of PSAT1 encoding phosphoserine aminotransferase 1, the second enzyme involved in de novo L-Ser synthesis. 6) Despite exhibiting such differing nervous symptoms as microcephaly, psychomotor retardation, and intractable seizures, patients with a genetic L-Ser deficiency have markedly decreased levels of L-and D-Ser in the cerebrospinal fluid and blood due to a mutation of PHGDH, PSAT1 or PSPH. 7) Although oral supplementation of L-and/or D-Ser is a potent therapeutic treatment for these patients, it is known that L-and D-Ser diffuse poorly through the blood-brain barrier.…”