Han Chinese patients with dopa-responsive dystonia exhibit a low frequency of exonic deletion in the GCH1 gene

Abstract

ABSTRACT. We identified three novel mutations of the GTP cyclohydrolase 1 (GCH1) gene in patients with familial dopa-responsive dystonia (DRD), but were unable to identify meaningful sporadic mutations in patients with no obvious family DRD background. To investigate whether GCH1 regional deletions account for the etiology of DRD, we screened for heterozygous exonic deletions in DRD families and in patients with sporadic DRD. Multiple ligation-dependent probe amplification analysis and quantitative real-time polymerase chain reaction amplification was performed in all members of our DRD cohort and in controls to detect exonic deletions in GCH1, tyrosine hydroxylase, and the epsilon-sarcoglycan-encoding (SGCE) genes. Using these techniques, we detected a GCH1 exon 1 heterozygous deletion in 1 of 10 patients with sporadic DRD. Therefore, we concluded that exonic deletion in the GCH1 gene only accounted for the etiology in a small percentage of patients with sporadic DRD in our Han Chinese cohort.

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“…GCH1 encodes the enzyme GTP cyclohydrolase I, which is a rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin (THB, BH4); the protein is critical for the generation of monoamine neurotransmitters such as serotonin (5-HT) and dopamine, as well as nitric oxide. Mutations of GCH1 are associated with multiple neuronal disorders including dopamine-responsive dystonia ( 57 – 59 ), neuropathic pain ( 60 , 61 ), and Parkinson’s disease ( 62 – 64 ). GCH1 is also implicated in cardiovascular functions, as suggested by the associations of genetic variants with endophenotypes, including nitric oxide excretion and cardiac autonomic traits ( 65 ).…”