Brat1-flox Mouse

BRAT1, also known as BRCA1-associated ataxia telangiectasia mutated activator 1, is involved in crucial biological processes. It participates in the DNA damage response and maintenance of mitochondrial homeostasis. BRAT1 also interacts with INTS11/INTS9 subunits of the Integrator complex, which is involved in regulating gene expression, especially of key neurodevelopmental genes. This interaction is essential for normal neural differentiation [2,3,4,6].

Mutations in BRAT1 are associated with a range of disorders. Biallelic variants can lead to rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). Genotype-phenotype correlations show that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe RMFSL phenotype, while genotypes with at least one missense are more likely associated with NEDCAS. Splice variants have a variable phenotype. Loss of BRAT1 function may decrease cell proliferation and migration and cause neuronal atrophy through impairment of mitochondrial homeostasis [1,2,5].

In conclusion, BRAT1 is vital for normal neurodevelopment and maintaining mitochondrial homeostasis. Studies on BRAT1-related mutations and their associated phenotypes, as well as the role of BRAT1 in gene regulation and neural differentiation, have enhanced our understanding of the pathophysiology of neurodevelopmental and neurodegenerative disorders associated with BRAT1 mutations.