01 December 2020
New autism-related gene identified
Published online 24 April 2020
Mutations in a gene involved in neuronal DNA and protein regulation may be a leading cause of inherited autism.
Autism spectrum disorder (ASD) represents a diverse group of neurodevelopmental disorders that affect around one per cent of children globally. ASD is known to run in families, suggesting that genetic mutations are a prominent cause. However, the complexity of ASD makes pinpointing its causative mechanisms a challenge.
An international team, led by Joseph Gleeson at the University of California and Gerald Crabtree at Stanford Medical School, US, and including a scientist at the National Research Center in Cairo, Egypt, has identified a mutated loss-of-function gene that appears to cause recessively inherited autism in a cohort of six Middle Eastern families.
The gene, ACTL6B, is part of the BAF complex – a group of molecules that work to remodel chromatin, the packages of DNA and proteins that regulate gene expression and activation. Previous studies have identified other BAF mutations linked with autism.
The team examined the role of ACTL6B using fly and mouse models, and a human brain organoid. Loss of ACTL6B function caused abnormal expression of early response genes and key proteins in mouse neurons. Humans and mice without functioning ACTL6B had poorly developed connective fibres between the two sides of the brain and ASD-related behaviours, including social and memory impairments, and hyperactivity.
“The gender and genetic background independence of ACTL6B mutations in both humans and mice should provide a powerful model for analysis of the role of chromatin regulation in autism,” the researchers conclude.
Wenderski, W. et al. Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism. PNAS http://dx.doi.org/10.1073/pnas.1908238117 (2020).