Functional characterization of the BRSK2 gene in regression-associated Autism Spectrum Disorder.

• Grant number: 25/02810-7
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2025
• End date: July 31, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Andréa Laurato Sertié
• Grantee: Raphaella Josino
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil

Abstract

Autism Spectrum Disorder (ASD) encompasses neurodevelopmental disorders that are clinically heterogeneous and of complex etiology, and may involve genetic and environmental risk factors. Within the spectrum, around 30% of cases show regression, defined as the loss of previously acquired social and communication skills. Although in recent years large-scale genomic studies have identified various loci and risk genes for ASD, the neurobiological mechanisms associated with the disorder and regression are still poorly understood. Recently, through whole exome sequencing of Brazilian individuals with ASD and their parents, we identified rare de novo variants in the BRSK2 (Brain-specific kinase 2) gene in two probands who showed regression. BRSK2 encodes a protein from the family of kinases, which regulate various cellular functions and are involved in processes related to neurodevelopment. Among the known functions of BRSK2 is axonal polarization and neuron maturation through the phosphorylation of proteins associated with neuronal microtubules, such as the TAU protein (whose deregulation is associated with neurodegenerative diseases). Our hypothesis is that the rare variants identified in the BRSK2 gene in individuals with regressive ASD alter early stages of brain development and lead to an atypical brain organization that is more susceptible to early neurodegeneration, especially under the influence of adverse environmental factors such as neuroinflammation, which contributes to the regression phenotype. Therefore, the main objectives of this project are to verify whether the rare variants identified in BRSK2 in individuals with regressive ASD are functional, affect early stages of neurodevelopment and lead to neurodegenerative phenotypes, particularly when exposed to inflammatory molecules. To this end, we will use as experimental models neural cells in monolayer cultures and three-dimensional brain organoids derived from induced pluripotent stem cells (iPSCs) obtained from individuals carrying rare variants in BRSK2, as well as iPSCs derived from control individuals genetically edited to knock out one of the copies of the BRSK2 gene (thus creating haploinsufficient lineages at this locus). These cell models will be exposed to inflammatory molecules. The results of this project will contribute to a deeper understanding of the mechanisms underlying the pathogenic variants found in patients with regressive ASD. (AU)