{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T17:04:31Z","timestamp":1779555871198,"version":"3.53.1"},"posted":{"date-parts":[[2026,5,21]]},"group-title":"Molecular Biology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["MH-103222"],"award-info":[{"award-number":["MH-103222"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    The single nucleotide polymorphism (SNP) rs1053230 within the kynurenine 3-monooxygenase (\n                    <jats:italic>KMO<\/jats:italic>\n                    ) gene encodes either an arginine (\n                    <jats:underline>C<\/jats:underline>\n                    GC) or cysteine (\n                    <jats:underline>T<\/jats:underline>\n                    GC) at amino acid residue 452. The rs1053230 genotype is associated with alterations in KMO expression and activity, and impaired cognition. Additionally, KMO intronic SNP rs2275163 is associated with schizophrenia endophenotypes. However, the direct functional consequences of these SNPs on KMO function have never been investigated.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Here we performed the first\n                    <jats:italic>in vitro<\/jats:italic>\n                    cell-based examination of the rs1053230 genotype on KMO expression, activity, cellular localisation and KMO-protein interactions, as well as examination of the effects of rs1053230 on schizophrenia-relevant clinical measures. We also examined the effects of rs2275163 genotype on\n                    <jats:italic>KMO<\/jats:italic>\n                    pre-mRNA stability and alternative splicing.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    HEK293T cells expressing KMO-Arg452 or KMO-Cys452 with a red fluorescent protein (RFP) tag produced equivalent levels of KMO mRNA, protein and enzymatic activity, and localised to mitochondria to the same extent. However, cycloheximide-mediated inhibition of protein translation revealed a striking reduction in protein stability of KMO-Arg452-RFP. KMO-RFP-trap pull-down followed by tandem liquid-chromatography-mass spectrometry (LC-MS\/MS) identified dramatic differences in protein partners between KMO variants. Indeed, gene ontology-term enrichment analysis revealed that terms associated with synaptic function were more highly enriched amongst KMO-Cys452 interacting proteins. rs1053230 genotype was found to associate with chronic, trait-like depressive mood symptoms in patients. rs2275163 genotype had no effect on\n                    <jats:italic>KMO<\/jats:italic>\n                    pre-mRNA.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Differences in protein stability and protein-protein interactions may underlie the mechanisms by which the KMO rs1053230 genotype influences neuronal function, leading to cognitive differences in psychiatric conditions.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.19.726163","type":"posted-content","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T22:55:21Z","timestamp":1779404121000},"source":"Crossref","is-referenced-by-count":0,"title":["The single nucleotide polymorphism rs1053230 modulates kynurenine 3-monooxygenase stability and is associated with cognitive and mood phenotypes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2088-4013","authenticated-orcid":false,"given":"Mary E W","family":"Collier","sequence":"first","affiliation":[{"name":"Division of Genetics and Genome Biology, University of Leicester, University Road, Leicester, LE1 7RH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Ceeney","sequence":"additional","affiliation":[{"name":"School of Chemistry, University of Leicester, University Road, Leicester, LE1 7RH, UK; Leicester Institute for Structural & Chemical Biology, Henry Wellcome Building, Lancaster Road, 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