caa a22 4500 397573715 CHVBK 20180308164848.0 cr unu---uuuuu 161202e199607 xx s 000 0 eng 10.1093/hmg/5.7.1023 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.7.1023 Recessively Inherited L-DOPA-Responsive Parkinsonism In Infancy Caused by A Point Mutation (L205p) in the Tyrosine Hydroxylase Gene [Elektronische Daten] [Barbara Lüdecke, Per M. Knappskog, Peter T. Clayton, Robert A. H. Surtees, James D. Clelland, Simon J. R. Heales, Michael P. Brand, Klaus Bartholomé, Torgeir Flatmark] Tyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of dopamine. This report describes a missense point mutation in the human TH (hTH) gene in a girl presenting parkinsonian symptoms in early infancy and a very low level of the dopamine metabolite homovanillic acid in the CSF. DNA sequencing revealed a T614-to-C transition in exon 5 (L205P). Both parents and the patient's brother are heterozygous for the mutation. Site-directed mutagenesis and expression in different systems revealed that the recombinant mutant enzyme had a low homospecific activity, i.e. ∼1.5% of wt-hTH in E. coli and ∼16% in a cell-free in vitro transcription-translation system. When transiently expressed in human embryonic kidney (A293) cells a very low specific activity (∼ 0.3% of wt-hTH) and immunoreactive hTH (<2%) was obtained. The expression studies are compatible with the severe clinical phenotype of the L205P homozygous patient carrying this recessively inherited mutation. Treatment with L-DOPA resulted in normalisation of the CSF homovanillic acid concentration and a sustained improvement in parkinsonian symptoms. © 1996 Oxford University Press Lüdecke Barbara University Children's Hospital, 44791 Bochum, Germany aut Knappskog Per M. Department of Biochemistry and Molecular Biology, University of Bergen, 5009 Bergen, Norway aut Clayton Peter T. Hospital for Sick Children, Great Ormond Street, Institute of Child Health, London WC1N 1EH, UK aut Surtees Robert A. H. Hospital for Sick Children, Great Ormond Street, Institute of Child Health, London WC1N 1EH, UK aut Clelland James D. Hospital for Sick Children, Great Ormond Street, Institute of Child Health, London WC1N 1EH, UK aut Heales Simon J. R. Institute of Neurology, London WC1N 3BG, UK aut Brand Michael P. Institute of Neurology, London WC1N 3BG, UK aut Bartholomé Klaus University Children's Hospital, 44791 Bochum, Germany aut Flatmark Torgeir Department of Biochemistry and Molecular Biology, University of Bergen, 5009 Bergen, Norway aut Human Molecular Genetics Oxford University Press 5/7(1996-07), 1023-1028 0964-6906 5:7<1023 1996 5 hmg https://doi.org/10.1093/hmg/5.7.1023 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.7.1023 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lüdecke Barbara University Children's Hospital, 44791 Bochum, Germany aut NATIONALLICENCE 700 1- Knappskog Per M. Department of Biochemistry and Molecular Biology, University of Bergen, 5009 Bergen, Norway aut NATIONALLICENCE 700 1- Clayton Peter T. Hospital for Sick Children, Great Ormond Street, Institute of Child Health, London WC1N 1EH, UK aut NATIONALLICENCE 700 1- Surtees Robert A. H. Hospital for Sick Children, Great Ormond Street, Institute of Child Health, London WC1N 1EH, UK aut NATIONALLICENCE 700 1- Clelland James D. Hospital for Sick Children, Great Ormond Street, Institute of Child Health, London WC1N 1EH, UK aut NATIONALLICENCE 700 1- Heales Simon J. R. Institute of Neurology, London WC1N 3BG, UK aut NATIONALLICENCE 700 1- Brand Michael P. Institute of Neurology, London WC1N 3BG, UK aut NATIONALLICENCE 700 1- Bartholomé Klaus University Children's Hospital, 44791 Bochum, Germany aut NATIONALLICENCE 700 1- Flatmark Torgeir Department of Biochemistry and Molecular Biology, University of Bergen, 5009 Bergen, Norway aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/7(1996-07), 1023-1028 0964-6906 5:7<1023 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford