Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8574, Japan.
Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, 183-0042, Japan.
Parkinsonism Relat Disord. 2024 Jul;124:107018. doi: 10.1016/j.parkreldis.2024.107018. Epub 2024 May 27.
DYT-KMT2B, also known as DYT28, is a childhood-onset hereditary dystonia caused by KMT2B mutation. The pathogenesis of DYT-KMT2B involves haploinsufficiency of KMT2B, an enzyme that catalyzes specific histone methylation (H3K4me3). Dysmorphic features in patients with DYT-KMT2B suggest that KMT2B dysfunction may extend beyond the neuronal system. Therefore, valuable diagnostic insights may be obtained from readily available tissue samples.
To explore the altered H3K4me3 levels in non-neural tissue of DYT-KMT2B patients.
A database analysis was performed to determine in which parts of the body and in which cells KMT2B is highly expressed. Twelve clinically and genetically diagnosed patients with DYT-KMT2B and 12 control subjects participated in this study. Oral mucosa-derived purified histone proteins were analyzed using Western blotting with anti-H3K4me3 and anti-H4 antibodies.
Higher expression of KMT2B was observed in oral keratinocytes and gingival fibroblasts, constituting the oral mucosa. In oral mucosa analyses, DYT-KMT2B cases exhibited markedly reduced H3K4me3 levels compared with the controls. Using a cutoff window of 0.90-0.98, the H3K4me3/H4 expression ratio was able to distinguish patient groups.
Oral mucosa H3K4me3 analysis is currently not sufficient as a diagnostic tool for DYT-KMT2B, but has the advantage for screening test since it is a non-invasive means.
DYT-KMT2B，也称为 DYT28，是一种由 KMT2B 突变引起的儿童起病的遗传性肌张力障碍。DYT-KMT2B 的发病机制涉及 KMT2B 的单倍不足，KMT2B 是一种催化特定组蛋白甲基化（H3K4me3）的酶。DYT-KMT2B 患者的畸形特征表明 KMT2B 功能障碍可能超出神经元系统。因此，从易得的组织样本中可能获得有价值的诊断见解。
探讨 DYT-KMT2B 患者非神经组织中 H3K4me3 水平的改变。
进行数据库分析以确定 KMT2B 在身体的哪些部位和哪些细胞中高度表达。本研究纳入了 12 名临床和基因诊断为 DYT-KMT2B 的患者和 12 名对照者。使用抗 H3K4me3 和抗 H4 抗体的 Western blot 分析从口腔黏膜中提取的纯化组蛋白蛋白。
在口腔角质形成细胞和牙龈成纤维细胞中观察到 KMT2B 的高表达，构成了口腔黏膜。在口腔黏膜分析中，与对照组相比，DYT-KMT2B 病例表现出明显降低的 H3K4me3 水平。使用 0.90-0.98 的截断窗口，H3K4me3/H4 表达比能够区分患者组。
目前，口腔黏膜 H3K4me3 分析尚不能作为 DYT-KMT2B 的诊断工具，但由于其是非侵入性手段，具有作为筛选试验的优势。
