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Am J Hum Genet. 2019 May 2;104(5):815-834. doi: 10.1016/j.ajhg.2019.03.022. Epub 2019 Apr 25.

Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons.

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Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada.
CHU-Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada.
Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC H3T 1J4, Canada.
Department of Pediatrics, Division of Medical Genetics, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
GeneDx, Gaithersburg, MD 20877, USA.
University of California at Davis Medical Center, Section of Medical Genomics, Sacramento, CA 95817, USA.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Departments of Medical Genetics and Paediatrics, Cumming School of Medicine, Alberta Children's Hospital and University of Calgary, Calgary, AB T3B 6A8, Canada.
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, WC1N 3BG London, UK.
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Education Center, Asahikawa Medical University, Asahikawa 078-8510, Japan.
Department of Pediatrics, St. Olav's Hospital, Trondheim University Hospital, Postbox 3250, Sluppen 7006 Trondheim, Norway.
Department of Medical Genetics, Haukeland University Hospital, 5021 Bergen, Norway.
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Genetics, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
McGill University, Department of Human Genetics, Montreal, QC H3G 0B1, Canada.
Division of Child Neurology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, UK.
Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, University Paris Diderot, Paris 75015, France.
Assistance Publique Hôpitaux de Paris (APHP), Robert Debré Hospital, Child and Adolescent Psychiatry Department, Paris, France.
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
Children's Rehabilitation Service, Mobile, AL 36604, USA.
Department of Neurology, University of Montreal, Montreal, QC, Canada.
Department of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
Department of Clinical Genetics, Addenbrookes Hospital, Cambridge CB2 0QQ, UK.
Institute of Human Genetics, University Medical Center Leipzig, 04103 Leipzig, Germany.
Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen 6500 GA, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
Department of Genetics, University Medical Center Utrecht, Utrecht & Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, the Netherlands.
Medical Genetics, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
Service de génétique clinique, Département de génétique médicale, Maladies rares et médecine personnalisée, Centre de Référence Anomalies du développement et Syndromes malformatifs du Sud-Ouest Occitanie Réunion, CHU de Montpellier, 34295 Montpellier Cedex 5, France.
Psychiatric Genetics Group, Douglas Hospital Research Institute, McGill University, Montreal, QC H4H 1R3, Canada. Electronic address:
CHU-Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:


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.


ACTL6B; genetic engineering; intellectual disability; neurodevelopment; seizure; stem cells

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