Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons.
Actins
/ genetics
Adult
Child
Child, Preschool
Chromatin
/ genetics
Chromosomal Proteins, Non-Histone
/ genetics
DNA-Binding Proteins
/ genetics
Dendrites
/ metabolism
Epilepsy
/ etiology
Female
Humans
Induced Pluripotent Stem Cells
/ metabolism
Infant
Male
Mutation
Neurodevelopmental Disorders
/ etiology
Neurons
/ metabolism
Young Adult
ACTL6B
genetic engineering
intellectual disability
neurodevelopment
seizure
stem cells
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
02 05 2019
02 05 2019
Historique:
received:
13
08
2018
accepted:
01
03
2019
pubmed:
30
4
2019
medline:
7
2
2020
entrez:
30
4
2019
Statut:
ppublish
Résumé
We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. 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-alleic 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.
Identifiants
pubmed: 31031012
pii: S0002-9297(19)30118-1
doi: 10.1016/j.ajhg.2019.03.022
pmc: PMC6507050
pii:
doi:
Substances chimiques
ACTL6B protein, human
0
Actins
0
Chromatin
0
Chromosomal Proteins, Non-Histone
0
DNA-Binding Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
815-834Subventions
Organisme : Medical Research Council
ID : MR/S01165X/1
Pays : United Kingdom
Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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