ACTL6B recessive

Molecular characteristics

The ACTL6B gene encodes a component of the neuron-specific BAF (nBAF) complex in postmitotic neurons. The nBAF complex has a role in chromatin remodelling and histone acetylation, which regulates gene expression during development, particularly in the process of dendritic outgrowth. This complex also contains BRG1 (SMARCA4; 603254) and BRM (SMARCA2; 600014).

Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-allelic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.