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Missense variants of human TH<\/jats:styled-content> are associated with a recessive neurometabolic disease with low levels of brain dopamine and noradrenaline, resulting in a variable clinical picture, from progressive brain encephalopathy to adolescent onset DOPA<\/jats:styled-content>\u2010responsive dystonia (DRD<\/jats:styled-content>). We expressed isoform 1 of human TH<\/jats:styled-content> (hTH<\/jats:styled-content>1) and its dystonia\u2010associated missense variants in E.\u00a0coli,<\/jats:italic> analysed their quaternary structure and thermal stability using size\u2010exclusion chromatography, circular dichroism, multi\u2010angle light scattering, transmission electron microscopy, small\u2010angle X\u2010ray scattering and assayed hydroxylase activity. Wild\u2010type (WT<\/jats:styled-content>) hTH<\/jats:styled-content>1 was a mixture of enzymatically stable tetramers (85.6%) and octamers (14.4%), with little interconversion between these species. We also observed small amounts of higher order assemblies of long chains of enzyme by transmission electron microscopy. To investigate the role of molecular assemblies in the pathogenesis of DRD<\/jats:styled-content>, we compared the structure of WT hTH<\/jats:styled-content>1 with the DRD<\/jats:styled-content>\u2010associated variants R410P and D467G that are found in vicinity of the predicted subunit interfaces. In contrast to WT hTH<\/jats:styled-content>1, R410P and D467G were mixtures of tetrameric and dimeric species. Inspection of the available structures revealed that Arg\u2010410 and Asp\u2010467 are important for maintaining the stability and oligomeric structure of TH<\/jats:styled-content>. Disruption of the normal quaternary enzyme structure by missense variants is a new molecular mechanism that may explain the loss of TH<\/jats:styled-content> enzymatic activity in DRD<\/jats:styled-content>. Unstable missense variants could be targets for pharmacological intervention in DRD<\/jats:styled-content>, aimed to re\u2010establish the normal oligomeric state of TH.<\/jats:p><\/jats:sec>\nimage<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14624","type":"journal-article","created":{"date-parts":[[2018,11,9]],"date-time":"2018-11-09T11:19:31Z","timestamp":1541762371000},"page":"291-306","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["The quaternary structure of human tyrosine hydroxylase: effects of dystonia\u2010associated missense variants on oligomeric state and enzyme activity"],"prefix":"10.1111","volume":"148","author":[{"given":"Peter D.","family":"Szigetvari","sequence":"first","affiliation":[{"name":"Department of Biomedicine University of Bergen Bergen Norway"},{"name":"K.G. 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Jebsen Centre for Research on Neuropsychiatric Disorders University of Bergen Bergen Norway"},{"name":"Department of Clinical Science University of Bergen Bergen Norway"},{"name":"Center for Medical Genetics and Molecular Medicine Haukeland University Hospital Bergen Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petri","family":"Kursula","sequence":"additional","affiliation":[{"name":"Department of Biomedicine University of Bergen Bergen Norway"},{"name":"Faculty of Biochemistry and Molecular Medicine University of Oulu Oulu Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Haavik","sequence":"additional","affiliation":[{"name":"Department of Biomedicine University of Bergen Bergen Norway"},{"name":"K.G. 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