Abnormal H3K4 enzyme catalytic activity and neuronal morphology caused by ASH1L mutations in individuals with Tourette syndrome

ASH1L potentially contributes to Tourette syndrome (TS) and other neuropsychiatric disorders, as our previous studies have shown. It regulates essential developmental genes by counteracting polycomb-mediated transcriptional repression, which restricts chromatin accessibility at target genes. ASH1L is highly expressed in the adult brain, playing a crucial role in the early stage. However, it remains unclear how ASH1L mutations carried by patients with TS participate in regulating neuronal growth processes leading to TS traits. Five TS families recruited in our study underwent comprehensive physical examinations and questionnaires to record clinical phenotypes and environmental impact factors. We validated the variants via Sanger sequencing and constructed two mutants near the catalytic domain of ASH1L. We conducted molecular modeling, in vitro assays, and primary neuron cultures to find the role of ASH1L in neuronal development and its correlation with TS. In this study, we validated five pathogenic ASH1L rare variants and observed symptoms in patients with simple tics and behavioral comorbidities. Mutations near the catalytic domain of TS patients cause mental state abnormalities and disrupt ASH1L function by destabilizing its spatial conformation, leading to decreased activity of catalytic H3K4, thereby affecting the neurite growth. We need to conduct larger-scale studies on TS patients and perform additional neurological evaluations on mature neurons. We first reported the effects of ASH1L mutations in TS patients, including phenotypic heterogeneity, protein function, and neurological growth. This information contributes to understanding the neurodevelopmental pathogenesis of TS in patients with ASH1L mutations.