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dc.contributor.authorFossbakk, Agneteen_US
dc.contributor.authorKleppe, Runeen_US
dc.contributor.authorKnappskog, Peren_US
dc.contributor.authorMartinez, Auroraen_US
dc.contributor.authorHaavik, Janen_US
dc.description.abstractCongenital tyrosine hydroxylase deficiency (THD) is found in autosomal-recessive Dopa-responsive dystonia and related neurological syndromes. The clinical manifestations of THD are variable, ranging from early-onset lethal disease to mild Parkinson disease-like symptoms appearing in adolescence. Until 2014, approximately 70 THD patients with a total of 40 different disease-related missense mutations, five nonsense mutations, and three mutations in the promoter region of the tyrosine hydroxylase (TH) gene have been reported. We collected clinical and biochemical data in the literature for all variants, and also generated mutant forms of TH variants previously not studied (N = 23). We compared the in vitro solubility, thermal stability, and kinetic properties of the TH variants to determine the cause(s) of their impaired enzyme activity, and found great heterogeneity in all these properties among the mutated forms. Some TH variants had specific kinetic anomalies and phenylalanine hydroxylase, and Dopa oxidase activities were measured for variants that showed signs of altered substrate binding. p.Arg233His, p.Gly247Ser, and p.Phe375Leu had shifted substrate specificity from tyrosine to phenylalanine and Dopa, whereas p.Cys359Phe had an impaired activity toward these substrates. The new data about pathogenic mechanisms presented are expected to contribute to develop individualized therapy for THD patients.en_US
dc.relation.ispartof<a href="" target="blank">Human tyrosine hydroxylase: Oxygen dependence and role in Dopa responsive dystonia</a>
dc.rightsAttribution-NonCommercial-NoDerivs CC BY-NC-NDeng
dc.subjecttyrosine hydroxylase deficiencyeng
dc.subjectDopa responsive dystoniaeng
dc.titleFunctional studies of tyrosine hydroxylase missense variants reveal distinct patterns of molecular defects in dopa-responsive dystoniaen_US
dc.typePeer reviewed
dc.typeJournal article
dc.rights.holderCopyright 2014 The Authors
dc.source.journalHuman Mutation
dc.subject.nsiVDP::Medical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714eng
dc.subject.nsiVDP::Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714nob

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