Neurodegenerative Brain Diseases Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
Mov Disord. 2012 Sep 15;27(11):1451-6. doi: 10.1002/mds.25147. Epub 2012 Sep 13.
Autosomal dominant dopa-responsive dystonia (AD-DRD) is caused by a biochemical defect primarily resulting from guanosine triphosphate cyclohydrolase 1 gene (GCH1) mutations. Few families have been reported without mutations in GCH1.
Genome-wide linkage analysis and positional cloning to identify the genetic defect in a Belgian AD-DRD family was carried out.
In this study, we report on the identification and characterization of a novel 24-kb deletion spanning exon 1 and the 5' regulatory region of GCH1 causing a wide spectrum of motor and nonmotor symptoms in a large Belgian AD-DRD family. This large-scale deletion of regulatory sequences leads to decreased GCH1 activity in all carriers, most probably resulting from allelic loss of transcription. We mapped the breakpoints of this deletion to the nucleotide level, allowing the development of a straightforward polymerase chain reaction assay for fast, efficient detection of this large deletion, which will prove valuable for preimplantation genetic diagnosis.
常染色体显性遗传多巴反应性肌张力障碍（AD-DRD）是由鸟苷三磷酸环化水解酶 1 基因（GCH1）突变引起的生化缺陷引起的。少数家族报告没有 GCH1 突变。
进行全基因组连锁分析和定位克隆，以确定一个比利时 AD-DRD 家族的遗传缺陷。
在这项研究中，我们报告了一个新的 24kb 缺失的鉴定和特征，该缺失跨越 GCH1 的外显子 1 和 5'调控区，导致一个大型比利时 AD-DRD 家族中广泛的运动和非运动症状。这种调节序列的大规模缺失导致所有携带者的 GCH1 活性降低，很可能是由于转录的等位基因丢失所致。我们将该缺失的断点定位到核苷酸水平，开发了一种简单的聚合酶链反应检测方法，用于快速、有效地检测这种大片段缺失，这对于植入前遗传诊断将非常有价值。
