Hereditary progressive dystonia (HPD) is caused by the mutant gene encoding GTP cyclohydrolase I (GCH). The clinical presentation of this disease varies considerably, and many cases appear to be sporadic. We have previously proposed that this clinical variation may be due to digetential expression of the mutant and normal GCH mRNA, presumably at the protein level. To provide support for this proposal, we studied a new Japanese family with HPD, in which 2 members were heterozygous for an exon-skipping mutation. This mutation produced truncated GCH, which s h e d 180-&0 acid residues at the amino terminus of the normal enzyme (GCH180). An affected heterozygote had a higher mutandnormal mRNA ratio than an unaffeaed heterozygote, consistent with our previous finding in the HPD M y with GCHl14. A further study, using coexpression of the mutant with wild-type GCH in COS-7 cells, showed that three mutant GCHs inactivated the normal enzyme. GCH114 was most effective in enzyme inactivation, which was followed by GCH180 and a normally occurring mutant GCH209. These results suggested that the dominant negative a c t of a mutant GCH on the normal enzyme might be one of the molecular mechanisms determining the heterogeneity of clinical phenotypes of HPD.
Hirano M, Yanagihara T, Ueno S. Dominant negative effect of GTP cyclohydrolase I mutations in dopa-responsive hereditary progressive dystonia.