Study On The Mutations In GTP Cyclohydrolase Ⅰ Gene In The Patients With Dopa Responsive Dystonia

Background: DRD accounts for about 5% of all childhood onset dystonia. It is a syndrome characterized by a dramatic and sustained response to relatively low doses of L-dopa. GCHlgene is one of its causative genes and catalyzes the initial and rate limiting step in the biosynthesis of BH4, which is the natural cofactor for TH. Mutations in GCH1 gene result in reduced GCH1 activity and thus in decreased synthesis of BH4. This hi turn compromises activity of TH and DA synthesis.Objective: To search for mutations in the coding region of the GCH1 gene in Chinese patients with DRD.Methods: Two families with five affected family members and six patients with sporadic DRD were examined. Mutation screening was performed using single-strand conformation polymorphism analysis followed by direct sequencing of the presumably mutated exons; in patients whose results showed a normal pattern on single-strand conformation polymorphism analysis, the entire coding region of the GCH1 gene was sequenced. To confirm the mutation, a pair of primers was designed, which produced a restrictive site for Sphl.Results: DNA sequencing revealed a new heterozygous A224 -G missense mutation (Tyr75 - Cys) located within exon 1 in one family with autosomal-dominant inheritance. This mutation is predicted to cause an amino acid change in the highly conserved region of the gene. The mutation was confirmed with restriction enzyme analysis; it was not present in 20 control alleles. hi patients from the other family and in patients with sporadic DRD, no alterations in the translated portion of the GCH1 gene were observed. Direct sequencing also showed that there exists gene polymorphism in intron 1 and intron 2 in Chinese.Conclusions: We describe a new missense mutation (A224 -G, Tyr75 -Cys) in the GCHl gene. Mutations in the coding region of the gene account for a part of patients with DRD.