Phenotypic exploration of Mice with a Point Mutation in BRAT1

Background BRAT1 (BRCA1-associated ataxia telangiectasia mutated activator 1) plays a crucial role in several vital biological processes, including the DNA damage response and the maintenance of mitochondrial homeostasis. Dysfunction in BRAT1 leads to a range of clinical phenotypes, with the majority of affected individuals succumbing before reaching one year of age. Results Through an analysis of previous literature, the homozygous BRAT1 p.V62E mutation (GTG to GAG) was selected to construct a mouse model. Homozygous BRAT1 p.V62E knock-in mice with a C57BL/6J background were generated using CRISPR/Cas9 technology, and the point mutation was confirmed by Sanger sequencing. The results revealed no significant differences between the mutant mice and wild-type controls during low-intensity testing. However, the mutant mice exhibited enhanced endurance during high-intensity testing. RNA sequencing analysis identified ten differentially expressed genes in the gastrocnemius muscle and four differentially expressed genes in the brain tissue of the mutant mice. Conclusions This represents the first successful construction of a BRAT1 mutant mouse model. This achievement not only provides confidence for developing additional mouse models but also offers a valuable perspective for understanding the relationship between BRAT1 and mitochondrial function. The mouse model demonstrates a degree of consistency with the clinical phenotypes observed in patients and may serve as a predictive tool for patient prognosis.