Deleterious Variation in BR Serine/Threonine Kinase 2 Classified a Subtype of Autism

Abstract

Recently, deleterious variants in the BR serine/threonine kinase 2 (BRSK2) gene have been reported in patients with autism spectrum disorder (ASD), suggesting that BRSK2 is a new high-confidence ASD risk gene, which presents an opportunity to understand the underlying neuropathological mechanisms of ASD. In this study, we performed clinical and neurobehavioral evaluations of a proband with a de novo non-sense variant in BRSK2 (p.R222X) with other reported BRSK2 mutant patients. To validate BRSK2 as an ASD risk gene, we generated a novel brsk2b-deficient zebrafish line through CRISPR/Cas9 and characterized its morphological and neurobehavioral features as well as performed molecular analysis of neurogenesis-related markers. The proband displayed typical ASD behaviors and language and motor delay, which were similar to other published BRSK2 mutant patients. Morphologically, brsk2b–/– larvae exhibited a higher embryonic mortality and rate of pericardium edema, severe developmental delay, and depigmentation as well as growth retardation in the early developmental stage. Behaviorally, brsk2b–/– zebrafish displayed significantly decreased activity in open field tests and enhanced anxiety levels in light/dark tests and thigmotaxis analysis. Specifically, brsk2b–/– zebrafish showed a prominent reduction of social interaction with peers and disrupted social cohesion among homogeneous groups. Molecularly, the mRNA expression levels of homer1b (a postsynaptic density scaffolding protein), and mbpa, mpz, and plp1b (molecular markers of oligodendrocytes and myelination) were increased in the brain tissues of adult brsk2b–/– zebrafish, while the expression level of isl1a, a marker of motor neurons, was decreased. Taken together, for the first time, we established a novel brsk2b-deficient zebrafish model that showed prominent ASD-like behaviors. In addition, the disturbed mRNA expression levels of neurogenesis-related markers implied that the processes of postsynaptic signaling as well as oligodendrocytes and myelination may be involved. This discovery may suggest a path for further research to identify the underlying neuropathological mechanisms between BRSK2 and ASD.

Case report: A novel frameshift mutation in BRSK2 causes autism in a 16-year old Chinese boy

“…The protein comprises multiple domains, including a proline-rich domain (aa 424-468), a kinase-associated domain (KA1; aa 530-653), a protein kinase (aa 19-270), and a ubiquitin-associated domain (UBA; aa 297-339) ( 18 ). BRSK2 is highly conserved in evolution and exclusively expressed in the vertebrate brain ( 14 ). In fact, BRSK2 is involved in axonogenesis and cortical neuron polarization ( 4 , 6 , 19 , 20 ).…”

“…The BRKS2 knockout mice died within a few days after birth ( 10 ). Meanwhile, BRSK2-mutant zebrafish exhibited ASD-like features (e.g., developmental delay, social impairment) ( 4 , 14 ).…”

Whole genome analysis of rare deleterious variants adds further evidence to BRSK2 and other risk genes in Autism Spectrum Disorder

“…BRSK2 encodes for a serine/threonine-protein kinase involved in axonogenesis and polarization of cortical neurons. Its role in neurodevelopment has been studied in mice models 29 and, most recently, in a brsk2-deficient zebrafish model that showed ASD-like behaviours 30 .…”

Genome-wide detection of positive and balancing selection signatures shared by four domesticated rainbow trout populations (Oncorhynchus mykiss)

“…In total, we identified 7 genes as primarly associated to neural and brain development in both regions detected under positive selection ( tsnare1, cdk14, brsk2a, auts2, brd2, znf135, and grxcr1 ). Some genes ( brsk2a, znf135, grxcr1, auts2; Table 6 ), related to brain development may induce behavior modifications in farmed animals, that may be related to domestication processes (Pasquet, 2018; Milla et al, 2021; Deng et al, 2022; Liu et al, 2022). This is in line with Żarski et al (2020) study showing that domestication modulates gene expression involved in neurogenesis.…”