Detection of Modified Histones from Oral Mucosa of a Patient with DYT-KMT2B Dystonia

Introduction: DYT-KMT2B is a rare childhood-onset, hereditary movement disorder typically characterized by lower-limb dystonia and subsequently spreads into the craniocervical and laryngeal muscles. Recently, KMT2B-encoding lysine (K)-specific histone methyltransferase 2B was identified as the causative gene for DYT-KMT2B, also known as DYT28. In addition to the fact that many physicians do not have sufficient experience or knowledge of hereditary dystonia, the clinical features of DYT-KMT2B overlap with those of other hereditary dystonia, and limited clinical biomarkers make the diagnosis difficult. Methods: Histone proteins were purified from the oral mucosa of patients with de novo KMT2B mutation causing premature stop codon, and then trimethylated fourth lysine residue of histone H3 (H3K4me3) which was catalyzed by KMT2B was analyzed by immunoblotting with specific antibody. We further analyzed the significance of H3K4me3 in patients with DYT-KMT2B using publicly available datasets. Results: H3K4me3 histone mark was markedly lower in the patient than in the control group. Additionally, a reanalysis of publicly available datasets concerning DNA methylation also demonstrated that KMT2B remained inactive in DYT-KMT2B. Discussion: Although only one case was studied due to the rarity of the disease, the reduction of H3K4me3 in the patient's biological sample supports the dysfunction of KMT2B in DYT-KMT2B. Together with informatics approaches, our results suggest that KMT2B haploinsufficiency contributes to the DYT-KMT2B pathogenic process.