Exon Skipping Caused by a Base Substitution at a Splice Site in the GTP Cyclohydrolase I Gene in a Japanese Family with Hereditary Progressive Dystonia/DOPA-Responsive Dystonia

Abstract

We report a novel mutation at a splice site in the GTP cyclohydrolase I gene in a Japanese family with hereditary progressive dystonia with marked diurnal fluctuation (HPD)/ dopa responsive dystonia (DRD). Reverse transcriptase-initiated PCR (RT-PCR) of lymphocyte mRNA showed both normal and small size fragments in the HPD patient and his asymptomatic mother. Sequence analysis revealed that skip splicing of exon 1 to exon 3 occurred in the small fragment. The patient and his mother were heterozygous for G→C substitution at conserved consensus sequence GT at 5′ end of the intron 2. Quantitative RT-PCR showed that the expression of normal GTP cyclohydrolase I mRNA decreased in their lymphocytes, while the HPD patient had more expression of mutant GTP cyclohydrolase I mRNA than his asymptomatic mother.