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

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...

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Bibliographic Details
Published in:Human molecular genetics 1996-07, Vol.5 (7), p.1023-1028
Main Authors: Lüdecke, Barbara, Knappskog, Per M., Clayton, Peter T., Surtees, Robert A. H., Clelland, James D., Heales, Simon J. R., Brand, Michael P., Bartholomé, Klaus, Flatmark, Torgeir
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cell Line
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
DNA Mutational Analysis
Escherichia coli - genetics
Exons - genetics
Female
Gene Expression
Genes - genetics
Humans
Infant
Kidney - embryology
Levodopa - therapeutic use
Medical sciences
Molecular Weight
Neurology
Parkinson Disease - drug therapy
Parkinson Disease - enzymology
Parkinson Disease - genetics
Parkinson Disease - physiopathology
Point Mutation - genetics
Recombinant Fusion Proteins - biosynthesis
Recombinant Fusion Proteins - chemistry
RNA, Messenger - analysis
Transfection
Tyrosine 3-Monooxygenase - chemistry
Tyrosine 3-Monooxygenase - genetics
Tyrosine 3-Monooxygenase - metabolism
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Summary: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 (
ISSN:0964-6906
1460-2083
1460-2083
DOI:10.1093/hmg/5.7.1023