Hirano Makito, Samukawa Makoto, Miyatake Satoko, Yamagishi Yuko, Isono Chiharu, Yoshikawa Rino, Saigoh Kazumasa, Terayama Atsushi, Higashimoto Yuji, Koshimizu Eriko, Mizuguchi Takeshi, Fujii Kanako, Mitsui Yoshiyuki, Matsumoto Naomichi, Nagai Yoshitaka
Department of Neurology, Kindai University Faculty of Medicine, Osaka, Japan.
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Front Neurol. 2025 Jul 22;16:1606305. doi: 10.3389/fneur.2025.1606305. eCollection 2025.
The genetic etiology of Parkinson's disease (PD) is complex; approximately 10% of patients with PD have various gene mutations that lead to familial forms of the disease. Recent analyses of non-coding repeat regions revealed that many neurodegenerative diseases are associated with pathological expansions. We evaluated the genetic background of non-coding repeat expansions in Japanese patients with PD.
We collected blood samples from 203 Japanese patients with PD and analyzed various non-coding repeat genes, including , and , using PCR-Sanger sequencing, repeat-primed PCR assay, and long-read sequencing.
Three patients with PD (1.5%) were found to have heterozygous repeat expansions in the gene causative of spinocerebellar ataxia type 8 and is associated with long non-coding RNA. One (0.5%) patient had compound heterozygous repeat expansions (AAGGG and ACAGG) in , the gene causative of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, which encodes a DNA repair protein. No patient had repeat expansions in or . All patients with repeat expansions exhibited typical parkinsonism with relatively rare subjective dysphagia, which was confirmed by videofluoroscopic results. Functional imaging, such as dopamine-transporter single photon emission computed tomography, showed abnormal findings in patients with non-coding repeat expansions.
Our findings revealed the importance of non-coding repeat expansions in Japanese patients with PD. This is the first study to show the positive result of non-coding repeat expansions in many patients with PD in Japan.
帕金森病（PD）的遗传病因复杂；约10%的PD患者有导致家族性疾病形式的各种基因突变。最近对非编码重复区域的分析表明，许多神经退行性疾病与病理性扩增有关。我们评估了日本PD患者中非编码重复扩增的遗传背景。
我们收集了203名日本PD患者的血样，并使用PCR-桑格测序、重复引物PCR检测和长读长测序分析了各种非编码重复基因，包括 、 和 。
发现3名PD患者（1.5%）在导致8型脊髓小脑共济失调且与长链非编码RNA相关的 基因中存在杂合重复扩增。1名（0.5%）患者在 基因中存在复合杂合重复扩增（AAGGG和ACAGG），该基因导致小脑共济失调、神经病变和前庭反射消失综合征，编码一种DNA修复蛋白。没有患者在 或 基因中有重复扩增。所有存在 重复扩增的患者均表现出典型的帕金森综合征，伴有相对罕见的主观吞咽困难，这通过电视荧光透视结果得到证实。功能成像，如多巴胺转运体单光子发射计算机断层扫描，在非编码重复扩增患者中显示出异常结果。
我们的研究结果揭示了非编码重复扩增在日本PD患者中的重要性。这是第一项在日本许多PD患者中显示非编码重复扩增阳性结果的研究。
