A splice mutation in the GTP cyclohydrolase I gene causes dopa-responsive dystonia by exon skipping.
Four different mutations in the GTP cyclohydrolase I gene were found (P199L, M211V, IVS5+1G>A, G203R) in 6 out of 33 families with dopa-responsive dystonia. A splice mutation (IVS5+1G>A) located at the border of exon 5 to intron 5 was found in one of these families. Three members of the family carry the IVS5+1G>A mutation on one allele, inherited from the father to the daughter and son. Examination of the mRNA showed an exon 5 skipping that results in a reduction of enzyme activity in cultured fibroblasts to 4-17% compared to controls. The father and daughter never had clinical symptoms of dopa-responsive dystonia. The son was symptomatic at the age of 3 years and was treated successfully with L-dopa/carbidopa. After 20 years this therapy was terminated and for the next 6 years he was free of symptoms. With increased motoric activity, symptoms reappeared and the therapy was reintroduced.
Skrygan
M
M
University Children's Hospital, Bochum, Germany.
Bartholomé
B
B
Bonafé
L
L
Blau
N
N
Bartholomé
K
K
D000483:Alleles; D000595:Amino Acid Sequence; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001483:Base Sequence; D001545:Benserazide / Q000627:therapeutic use; D001708:Biopterins / Q000378:metabolism; D002478:Cells, Cultured; D002675:Child, Preschool; D004295:Dihydroxyphenylalanine / Q000627:therapeutic use*; D004338:Drug Combinations; D004421:Dystonia / Q000188:drug therapy / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006136:GTP Cyclohydrolase / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007438:Introns; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D019798:Neopterin / Q000096:biosynthesis; D012326:RNA Splicing; D012333:RNA, Messenger / Q000032:analysis
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C005177:benserazide, levodopa drug combination; D001708:Biopterins; D007980:Levodopa; D004295:Dihydroxyphenylalanine; D019798:Neopterin; D001545:Benserazide; D006136:GTP Cyclohydrolase