Unraveling the impact of trip12 on neurodevelopment: insights from a zebrafish model

Thyroid Hormone Receptor Interactor 12 (TRIP12) is an E3 ubiquitin ligase capable of mediating ubiquitin-dependent proteolysis of specific protein substrates. This function regulates key biological processes, including cell cycle progression, cell differentiation, chromatin remodelling and DNA damage repair. Consequently, loss-of-function mutations in TRIP12 have been associated with a broad spectrum of human diseases, including cancer and neurological and neurodevelopmental disorders. Previous studies have demonstrated that pathological variants of TRIP12 cause Clark-Baraitser syndrome, characterized by craniofacial dysmorphism, motor delay and intellectual disability, with or without autism spectrum disorder. Despite the well-characterized clinical manifestations, the underlying molecular pathways affected by TRIP12 disruption and their implication in the pathophysiology of autism spectrum disorder and intellectual disability remain unclear. Using a knock-out zebrafish model, we have elucidated the essential role of trip12 in diverse metabolic and biological pathways, particularly those related to neural and neurodevelopmental processes, shedding light on potential mechanisms underlying the pathogenesis. Heterozygous and recessive homozygous zebrafish mutants exhibit clinical features analogous to those observed in human patients, including craniofacial anomalies and decreased locomotor activity. Furthermore, this study provides substantial evidence for the vital role of trip12 in the early stages of development, as homozygous individuals exhibited early mortality by Day 23 post-fertilization, while a substantial mortality rate of 90% was observed by Day 35 in 'heterozygous' mutants. The present study demonstrates the profound impact that trip12 mutations have on embryogenesis, and transcriptomic analysis offers an in-depth knowledge of the molecular basis of the disease. These findings offer valuable insights into potential therapeutic targets for improving outcomes in individuals with TRIP12-associated disorders.