Relevance to Autism

Analysis of 135 ASD probands from consanguineous marriages recruited for the Simons Recessive Autism Cohort (SRAC) in Wenderski et al., 2000 identified six families with segregating loss-of-function variants in ACTL6B; when considering all coding genes, ACTL6B showed genome-wide significance for variants in the SRAC. In the same report, Actl6b knockout mice on two genetic backgrounds displayed ASD-associated behaviors, including social and memory impairments, repetitive behaviors, hyperactivity, and hypoplasia of the corpus callosum. Bell et al., 2019 had previously demonstrated that individuals harboring biallelic mutations in the ACTL6B gene presented with a neurodevelopmental disorder characterized by global developmental delay, epileptic encephalopathy, axial hypotonia, and spasticity, whereas individuals with de novo heterozygous missense variants in the same gene presented with intellectual disability, developmental delay, delayed or absent speech, ambulation deficits, hypotonia, autism or autistic features, Rett-like stereotypies such as handwringing, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Homozygous variants in the ACTL6B gene had previously been identified in three individuals from two families presenting with severe developmental and epileptic encephalopathy in Fichera et al., 2019, as well as in two siblings presenting with intellectual disability, seizures, and autistic behaviors (Karaca et al., 2015) and a female patient diagnosed with atypical Rett syndrome (Sajan et al., 2017). A postzygotic mosaic coding-synonymous variant that was predicted to create a new exonic splicing site in the ACTL6B gene was observed in an ASD proband from the Simons Simplex Collection in Krupp et al., 2017.

Molecular Function

The protein encoded by this gene is a member of a family of actin-related proteins (ARPs) which share significant amino acid sequence identity to conventional actins. Both actins and ARPs have an actin fold, which is an ATP-binding cleft, as a common feature. The ARPs are involved in diverse cellular processes, including vesicular transport, spindle orientation, nuclear migration and chromatin remodeling. This gene encodes a subunit of the BAF (BRG1/brm-associated factor) complex in mammals, which is functionally related to SWI/SNF complex in S. cerevisiae and Drosophila; the latter is thought to facilitate transcriptional activation of specific genes by antagonizing chromatin-mediated transcriptional repression. This subunit may be involved in the regulation of genes by structural modulation of their chromatin, specifically in the brain.

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