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

TitleLoss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism.
Publication TypeJournal Article
Year of Publication2020
AuthorsWenderski, W, Wang, L, Krokhotin, A, Walsh, JJ, Li, H, Shoji, H, Ghosh, S, George, RD, Miller, EL, Elias, L, Gillespie, MA, Son, EY, Staahl, BT, Baek, STae, Stanley, V, Moncada, C, Shipony, Z, Linker, SB, Marchetto, MCN, Gage, FH, Chen, D, Sultan, T, Zaki, MAHS, Ranish, JA, Miyakawa, T, Luo, L, Malenka, RC, Crabtree, GR, Gleeson, JG
JournalProc Natl Acad Sci U S A
Date Published2020 05 05
KeywordsActins, Adenosine Triphosphate, Animals, Autism Spectrum Disorder, Behavior, Animal, Chromatin, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, Chromosome Pairing, Corpus Callosum, Dendrites, Disease Models, Animal, DNA-Binding Proteins, Gene Expression Regulation, Hippocampus, Humans, Mice, Mice, Knockout, Mutation, Neurons, Transcription Factors

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 (originally named ). Accordingly, 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 showed corpus callosum hypoplasia, indicating a conserved role for in facilitating neural connectivity. knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of relieved repression of early response genes including AP1 transcription factors (, , , and ), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.

Alternate JournalProc Natl Acad Sci U S A
PubMed ID32312822
PubMed Central IDPMC7211998
Grant ListU54 HG006504 / HG / NHGRI NIH HHS / United States
P50 DA042012 / DA / NIDA NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
T32 GM008666 / GM / NIGMS NIH HHS / United States
T32 GM007790 / GM / NIGMS NIH HHS / United States
F31 MH116588 / MH / NIMH NIH HHS / United States