Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism.

Abstract

Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such "early activation" genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit <i>ACTL6B</i> (originally named <i>BAF53b</i>). Accordingly, <i>ACTL6B</i> was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking <i>ACTL6B</i> showed corpus callosum hypoplasia, indicating a conserved role for <i>ACTL6B</i> in facilitating neural connectivity. <i>Actl6b</i> knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of <i>Actl6b</i> relieved repression of early response genes including AP1 transcription factors (<i>Fos</i>, <i>Fosl2</i>, <i>Fosb</i>, and <i>Junb</i>), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. <i>ACTL6B</i> loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.