Ohta Etsuro, Funayama Manabu, Ichinose Hiroshi, Toyoshima Itaru, Urano Fumi, Matsuo Mitsuhiro, Tomoko Nishida, Yukihiko Konishi, Yoshino Syuji, Yokoyama Hiroyuki, Shimazu Hideki, Maeda Koji, Hasegawa Kazuko, Obata Fumiya
Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, Department of Neurology, National Sagamihara Hospital, Sagamihara, Kanagawa, Japan.
Arch Neurol. 2006 Nov;63(11):1605-10. doi: 10.1001/archneur.63.11.1605.
To better understand the relationship between mutation of the guanosine triphosphate cyclohydrolase I (GCH1) gene and the etiology of DYT5 dystonia and to accumulate data on the mutation in the Japanese population for genetic diagnosis of the disease.
Japanese population. Patients Eight Japanese patients with suspected DYT5 dystonia were analyzed. Intervention Direct genomic sequencing of 6 exons of GCH1 was performed.
For patients who did not exhibit any abnormality in the sequence analysis, the possibility of exon deletions was examined. In cases for which cerebrospinal fluid was available, the concentrations of neopterin and biopterin were measured as an index of GCH1 enzyme activity.
In 2 patients, we found a new T106I mutation in exon 1 of GCH1, a position involved in the helix-turn-helix structure of the enzyme. In the third patient, we found a new mutation (a 15-base pair nucleotide deletion) in exon 5 that may cause a frameshift involving the active site. In the fourth patient, we detected a known nucleotide G>A substitution in the splice site of intron 5, which has been reported to produce exon 5-skipped messenger RNA. The concentrations of both neopterin and biopterin in the cerebrospinal fluid of the third and fourth patients were markedly lower than the normal range, indicating that the GCH1 enzyme was functionally abnormal in these mutations. Gene dosage analysis showed that the fifth patient had a deletion of both exon 3 and exon 4, whereas the sixth patient had a deletion of exon 3.
We found several novel, as well as known, GCH1 mutations in Japanese patients with DYT5 dystonia. In some of them, the GCH1 enzyme activity was proved to be impaired.
为了更好地理解三磷酸鸟苷环化水解酶I（GCH1）基因突变与DYT5型肌张力障碍病因之间的关系，并积累日本人群中该基因突变的数据以用于该病的基因诊断。
日本人群。患者 对8例疑似DYT5型肌张力障碍的日本患者进行了分析。干预措施 对GCH1基因的6个外显子进行直接基因组测序。
对于序列分析未显示任何异常的患者，检测外显子缺失的可能性。对于有脑脊液样本的患者，测量新蝶呤和生物蝶呤的浓度作为GCH1酶活性的指标。
在2例患者中，我们在GCH1基因第1外显子中发现了一个新的T106I突变，该位置参与酶的螺旋-转角-螺旋结构。在第3例患者中，我们在第5外显子中发现了一个新的突变（15个碱基对的核苷酸缺失），可能导致涉及活性位点的移码突变。在第4例患者中，我们在第5内含子的剪接位点检测到一个已知的核苷酸G>A替换，据报道该替换会产生跳过第5外显子的信使RNA。第3例和第4例患者脑脊液中新蝶呤和生物蝶呤的浓度均明显低于正常范围，表明这些突变中GCH1酶功能异常。基因剂量分析显示，第5例患者第3外显子和第4外显子均缺失，而第6例患者第3外显子缺失。
我们在日本DYT5型肌张力障碍患者中发现了几种新的以及已知的GCH1突变。其中一些突变中，GCH1酶活性被证实受损。
