Journal Article

Recessively Inherited L-DOPA-Responsive Parkinsonism In Infancy Caused by A Point Mutation (L205p) in the Tyrosine Hydroxylase Gene

Barbara Lüdecke, Per M. Knappskog, Peter T. Clayton, Robert A. H. Surtees, James D. Clelland, Simon J. R. Heales, Michael P. Brand, Klaus Bartholomé and Torgeir Flatmark

in Human Molecular Genetics

Volume 5, issue 7, pages 1023-1028
Published in print July 1996 | ISSN: 0964-6906
Published online July 1996 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/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

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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.

Journal Article.  4139 words.  Illustrated.

Subjects: Genetics and Genomics

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