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.