Relevance to Autism

BMAL1 (previously called ARNTL) was initially proposed as an autism candidate gene based on the identification of a missense variant that was predicted to be damaging in a Japanese ASD proband (Yang et al., 2016). A de novo frameshift variant in this gene was identified in an ASD proband from a simplex family from the AGRE cohort in Yuen et al., 2017, and an inherited nonsense variant in this gene was identified in an ASD proband from the iHART cohort in Ruzzo et al., 2019. A genome-wide association study (GWAS) of a sociability score based on four social functioning-related self-report questions from 342,461 adults in the UK Biobank and subsequent gene-wide and functional follow-up analyses in Bralten et al., 2021 found that the strongest association signal in the SNP-based GWAS was observed on chromosome 11p15 (rs34588274,p=1.01e13); this locus encompassed theBAML1gene. Liu et al., 2022 demonstrated that global deletion of this gene in mice led to significant social impairments, excessive stereotyped and repetitive behaviors, motor learning disabilities, and aberrant cell density, immature morphology of dendritic spines, and enhanced excitatory and inhibitory synaptic transmission and reduced firing rates in cerebellar Purkinje cells; furthermore, conditional deletion of this gene in cerebellar Purkinje cells was sufficient to recapitulate autistic-like behavioral and cellular changes akin to those identified in KO mice.

Molecular Function

The protein encoded by this gene is a basic helix-loop-helix protein that forms a heterodimer with CLOCK. This heterodimer binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Defects in this gene have been linked to infertility, problems with gluconeogenesis and lipogenesis, and altered sleep patterns.

External Links

References