Human Molecular Genetics Laboratory, Department of Medical Research, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan.
Am J Med Genet B Neuropsychiatr Genet. 2010 Jun 5;153B(4):903-8. doi: 10.1002/ajmg.b.31058.
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.
GCH1 基因的大片段缺失已在少数多巴反应性肌张力障碍 (DRD) 病例中报道。在这项研究中，我们对 8 个家系的 22 名受影响成员进行了广泛的临床和遗传研究。序列分析显示在 5 个家系中有 5 种不同的突变（n = 10）；Ser81Pro（新发现）、Ser76X、Gly203Arg、249delA 和 IVS5 + 3insT。应用多重连接依赖性探针扩增分析，我们在其余 3 个家系（n = 12）中检测到外显子 1-3 的大片段杂合缺失，这通过定量实时 PCR 分析得到了验证。因此，大片段缺失占总家系的 37.5%，占我们 DRD 人群的 55%。缺失似乎具有高外显率，与多灶性肌张力障碍和男性成年发病有关。成年发病的患者通常表现为静止性震颤、僵硬和运动迟缓，与帕金森病患者无法区分。总之，在台湾的 DRD 人群中发现了 GCH1 的多外显子缺失的高频率。通过剂量分析，我们能够在所有患者中检测到突变。我们的研究表明，剂量分析对于汉族 DRD 患者的分子诊断是必要的。
