S. N. Pradhan Centre for Neurosciences, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India.
J Neural Transm (Vienna). 2012 Nov;119(11):1343-50. doi: 10.1007/s00702-012-0777-z. Epub 2012 Feb 29.
The aim of this study is to examine the role of GCH1 among Indians affected with dopa responsive dystonia (DRD) and early onset Parkinson's disease (EOPD). The patients (n = 76 including 19 DRD and 36 EOPD) and controls (n = 138) were screened for variants in GCH1 by PCR amplification of exons, splice junctions and 1 kb upstream region followed by SSCP and DNA sequencing. Four novel variants (p.Met1Val, p.Val204_205del, IVS3+68A>G, and IVS5-6T>G) were identified in 10 patients but not in the controls. In addition to two nonsynonymous changes, identified in four DRD patients in heterozygous condition, one intronic variant (IVS5-6T>G) could be linked to pathogenesis of the disease since it has the potential of altering the splice site as assessed by in silico analysis. Patients carrying different nonsynonymous variants had remarkable variation in clinical phenotype. Consistent with earlier reports, severity of clinical phenotype and the age of onset varied among family members harboring the same mutation. No mutation was detected in the EOPD patients. Three novel mutations in GCH1 gene have been found and are shown to be associated with variable clinical phenotypes mostly within the spectrum of DRD. The mutations identified represent 15.79% (3/19) of east Indian DRD patient cohort.
本研究旨在探讨 GCH1 在印度多巴胺反应性肌张力障碍（DRD）和早发性帕金森病（EOPD）患者中的作用。通过对患者（n=76，包括 19 例 DRD 和 36 例 EOPD）和对照组（n=138）的 GCH1 基因外显子、剪接接头和 1kb 上游区域进行 PCR 扩增，然后进行 SSCP 和 DNA 测序，筛选出该基因的变异。在 10 名患者中发现了 4 种新的变异（p.Met1Val、p.Val204_205del、IVS3+68A>G 和 IVS5-6T>G），但在对照组中未发现。除了在 4 名杂合子 DRD 患者中发现的两种非同义突变外，一种内含子变异（IVS5-6T>G）也可能与疾病的发病机制有关，因为通过计算机分析评估，它有可能改变剪接位点。携带不同非同义变异的患者的临床表型有显著差异。与早期报道一致，携带相同突变的家族成员的临床表型严重程度和发病年龄也存在差异。EOPD 患者未检测到突变。在 GCH1 基因中发现了 3 种新的突变，这些突变与多变的临床表型有关，主要是在 DRD 范围内。鉴定出的突变占东印度 DRD 患者队列的 15.79%（3/19）。
