Steinberger D, Weber Y, Korinthenberg R, Deuschl G, Benecke R, Martinius J, Müller U
Institut für Humangenetik, Justus-Liebig-Universität, Giessen, Germany.
Ann Neurol. 1998 May;43(5):634-9. doi: 10.1002/ana.410430512.
We performed a clinical and molecular genetic analysis in members of five families with dopa-responsive dystonia. Four mutations were detected in the gene GCH1 that codes for GTP cyclohydrolase I. Two of these mutations, a delG309 in exon 1 and a C544T transition in exon 5, have not been described before. They result in inactivation of the enzyme by truncation. The remaining two mutations, both A to G transitions, a(-2)g in intron 1 and a(-2)g in intron 2, cause truncation by abnormal splicing. The genotype of family members was correlated to their clinical phenotype (obtained before molecular analysis). Clinical symptoms observed in the families included generalized and focal dystonia, abnormal gait, and subtle signs such as an abnormal writing test. High penetrance (0.8-1.0) was observed in four of five families if minor symptoms and signs were considered. A given mutation was more likely to cause symptoms in females than in males, thus confirming the well-established higher incidence of dopa-responsive dystonia in females than in males.
我们对五个患有多巴反应性肌张力障碍家族的成员进行了临床和分子遗传学分析。在编码GTP环化水解酶I的GCH1基因中检测到四个突变。其中两个突变，外显子1中的delG309和外显子5中的C544T转换，此前尚未见报道。它们通过截短导致酶失活。其余两个突变，均为A到G的转换，内含子1中的a(-2)g和内含子2中的a(-2)g，通过异常剪接导致截短。家族成员的基因型与其临床表型（分子分析前获得）相关。这些家族中观察到的临床症状包括全身性和局灶性肌张力障碍、异常步态以及诸如异常书写试验等细微体征。如果考虑轻微症状和体征，五个家族中有四个观察到高外显率（0.8 - 1.0）。特定突变在女性中比在男性中更易引发症状，从而证实了多巴反应性肌张力障碍在女性中比在男性中发病率更高这一已确立的情况。
