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 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. approximately 1.5% of wt-hTH in E. coli and approximately 16% in a cell-free in vitro transcription-translation system. When transiently expressed in human embryonic kidney (A293) cells a very low specific activity (approximately 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.
Lüdecke
B
B
University Children's Hospital, Bochum, Germany.
Knappskog
P M
PM
Clayton
P T
PT
Surtees
R A
RA
Clelland
J D
JD
Heales
S J
SJ
Brand
M P
MP
Bartholomé
K
K
Flatmark
T
T
D002460:Cell Line; D004252:DNA Mutational Analysis; D004926:Escherichia coli / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005796:Genes / Q000235:genetics; D006801:Humans; D007223:Infant; D007668:Kidney / Q000196:embryology; D007980:Levodopa / Q000627:therapeutic use*; D008970:Molecular Weight; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D017354:Point Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase