A heterozygous mutation in UBE2H in a patient with developmental delay leads to an aberrant brain development in zebrafish

Abstract

Background Ubiquitin-related rare diseases are generally characterized by developmental delays and mental retardation, but the exact incidence or prevalence is not yet fully understood. The clinical application of next-generation sequencing for pediatric seizures and developmental delay of unknown causes has become common in studies aimed at identification of a causal gene in patients with ubiquitin-related rare diseases that cannot be diagnosed using conventional fluorescence in situ hybridization or chromosome microarray tests. Our study aimed to investigate the effects of ubiquitin–proteasome system on ultra-rare neurodevelopmental diseases, through functional identification of candidate genes and variants. Methods In our present work, we carried out genome analysis of a patient with clinical phenotypes of developmental delay and intractable convulsion, to identify causal mutations. Further characterization of the candidate gene was performed using zebrafish, through gene knockdown approaches. Transcriptomic analysis using whole embryos of zebrafish knockdown morphants and additional functional studies identified downstream pathways of the candidate gene affecting neurogenesis. Results Through trio-based whole-genome sequencing analysis, we identified a de novo missense variant of the ubiquitin system-related gene UBE2H (c.449C>T; p.Thr150Met) in the proband. Using zebrafish, we found that Ube2h is required for normal brain development. Differential gene expression analysis revealed activation of the ATM-p53 signaling pathway in the absence of Ube2h. Moreover, depletion of ube2h led to induction of apoptosis, specifically in the differentiated neural cells. Finally, we found that a missense mutation in zebrafish, ube2h (c.449C>T; p.Thr150Met), which mimics a variant identified in a patient with neurodevelopmental defects, causes aberrant Ube2h function in zebrafish embryos. Conclusion A de novo heterozygous variant in the UBE2H c.449C>T (p.Thr150Met) has been identified in a pediatric patient with global developmental delay and UBE2H is essential for normal neurogenesis in the brain.

Identification and characterization of putative biomarkers and therapeutic axis in Glioblastoma multiforme microenvironment

“…Additionally, Ube2S is controlled by the PTEN/Akt pathway and participates in DNA repair, particularly NHEJ-mediated DNA repair, which makes chemotherapeutic drugs more sensitive to GBM ( Maksoud, 2021 ). In a recent study, Shin et al found a mutation ( de novo missense variant) that resembles a variant found in a patient with neurodevelopmental abnormalities, induces irregular Ube2h function in zebrafish embryos, and results in abnormal brain development ( Shin et al, 2023 ). In addition, according to Lim and Joo (2020) , circulating Ube2H mRNA is potentially used to diagnose and treat Alzheimer’s disease ( Lim and Joo, 2020 ).…”