title: High frequency of multiexonic deletion of the GCH1 gene in a Taiwanese cohort of dopa-response dystonia.
abstract: Large deletions in the GCH1 gene have been reported in a minority of cases of dopa-responsive dystonia (DRD). In this study, we performed an extensive clinical and genetic investigation of 22 affected members in eight families. Sequence analysis revealed five different mutations in five families (n = 10); Ser81Pro (novel), Ser76X, Gly203Arg, 249del A, and IVS5 + 3insT. Applying multiple ligation-dependent probe amplification analysis, we detected a large heterozygous deletion of exons 1-3 in the remaining three families (n = 12), which was verified by quantitative real-time PCR analysis. Therefore, the large deletion accounted for 37.5% of the total families and 55% of our DRD population. The deletion appeared to have high penetrance and was associated with multifocal dystonia and adult onset in males. Adult-onset patients were commonly presenting with resting tremor, rigidity, and bradykinesia, indistinguishable from those in Parkinson's disease. In conclusion, a high frequency of multiexonic deletion of GCH1 was identified in the Taiwanese DRD population. By dosage analysis, we were able to detect a mutation in all patients. Our study demonstrates that dosage analysis is necessary for molecular diagnostics in DRD patients of Han Chinese ethnicity.
authors.affiliation: Human Molecular Genetics Laboratory, Department of Medical Research, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan.
authors.forename: Yah-Huei
authors.initials: YH
authors.lastname: Wu-Chou
authors.forename: Tu-Hsueh
authors.initials: TH
authors.lastname: Yeh
authors.forename: Chuan-Yu
authors.initials: CY
authors.lastname: Wang
authors.forename: Juei-Jueng
authors.initials: JJ
authors.lastname: Lin
authors.forename: Chin-Chang
authors.initials: CC
authors.lastname: Huang
authors.forename: Hsiu-Chen
authors.initials: HC
authors.lastname: Chang
authors.forename: Szu-Chia
authors.initials: SC
authors.lastname: Lai
authors.forename: Rou-Shayn
authors.initials: RS
authors.lastname: Chen
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Weng
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Huang
authors.forename: Chin-Song
authors.initials: CS
authors.lastname: Lu
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004295:Dihydroxyphenylalanine / Q000235:genetics*; D004421:Dystonia / Q000235:genetics*; D020821:Dystonic Disorders / Q000235:genetics*; D005091:Exons; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics; D057089:Pathology, Molecular; D019683:Penetrance; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D004295:Dihydroxyphenylalanine