Two previously unrecognized splicing mutations of GCH1 in Dopa-responsive dystonia: exon skipping and one base insertion

ABSTRACT

We describe two previously unrecognized splice site mutations of GCH1 in Dopa responsive dystonia (DRD). Both mutations affect consensus splice acceptor (AG) sites. The first mutation is an A→G transition at position -2 of intron 1 of GCH1. This mutation results in skipping of exon 2. Fusion of exons 1 and 3 causes a frame shift that generates a premature stop codon. The second mutation is an A→G transition at position -2 of intron 2. The mutation generates a new splice acceptor site AG one base pair upstream of the wild-type splice site. This, together with a pyrimidine stretch upstream of the new splice site, renders this site functional and generates a transcript with the insertion of one base, i.e. the G of the wild-type splice site. This in turn causes a frame shift including the introduction of a premature stop codon. The two different mutations generate truncated GTP cyclohydrolase polypeptides.