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 dy stonia. A splice mutation (IVS5+1G >A) located at the border of exon 5 to i ntron 5 was found in one of these families. Three members of the family car ry 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 re sults in a reduction of enzyme activity in cultured fibroblasts to 4-17% co mpared 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 therap y was terminated and for the next 6 years he was free of symptoms. With inc reased motoric activity, symptoms reappeared and the therapy was reintroduc ed.