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

Scott Bell (1) , Justine Rousseau (2) , Huashan Peng (1) , Zahia Aouabed (1) , Pierre Priam (2) , Jean-Francois Theroux (1) , Malvin Jefri (1) , Arnaud Tanti (1) , Hanrong Wu (1) , Ilaria Kolobova (1) , Heika Silviera (1) , Karla Manzano-Vargas (1) , Sophie Ehresmann (2) , Fadi F. Hamdan (2) , Nuwan Hettige (1) , Xin Zhang (1) , Lilit Antonyan (1) , Christina Nassif (2) , Lina Ghaloul-Gonzalez (3) , Jessica Sebastian (3) , Jerry Vockley (3) , Amber G. Begtrup (4) , Ingrid M. Wentzensen (4) , Amy Crunk (4) , Robert D. Nicholls (3) , Kristin C. Herman (5) , Joshua L. Deignan (6) , Walla Al-Hertani (7) , Stephanie Efthymiou (8) , Vincenzo Salpietro (8) , Noriko Miyake (9) , Yoshio Makita (10) , Naomichi Matsumoto (9) , Rune Østern (11) , Gunnar Houge (12) , Maria Hafström (11) , Emily Fassi (13) , Henry Houlden (8) , Jolien S. Klein Wassink-Ruiter (14, 15) , Dominic Nelson (1) , Amy Goldstein (16) , Tabib Dabir (17) , Julien van Gils (18) , Thomas Bourgeron (18) , Richard Delorme (19) , Gregory M. Cooper (20) , Jose E. Martinez (21) , Candice R. Finnila (20) , Lionel Carmant (21) , Anne Lortie (2) , Renske Oegema (22) , Koen van Gassen (22) , Sarju G. Mehta (23) , Dagmar Huhle (23) , Rami Abou Jamra (24) , Sonja Martin (24) , Han G. Brunner (25, 26) , Dick Lindhout (22) , Margaret Au (27) , John M. Graham Jr. (27) , Christine Coubes (28) , Gustavo Turecki (1) , Simon Gravel (14, 15) , Naguib Mechawar (1) , Elsa Rossignol (2) , Jacques L. Michaud (2) , Julie Lessard (2) , Carl Ernst (1) , Philippe M. Campeau (2)

1 McGill University = Université McGill [Montréal, Canada]
2 UdeM - Université de Montréal
3 PITT - University of Pittsburgh
4 GeneDx [Gaithersburg, MD, USA]
5 UC Davis - University of California [Davis]
6 David Geffen School of Medicine [Los Angeles]
7 University of Calgary
8 UCL, Institute of Neurology [London]
9 YCU - Yokohama City University
10 Asahikawa Medical College
11 Trondheim University
12 Haukeland University Hospital
13 Washington University School of Medicine in St. Louis
14 University of Groningen [Groningen]
15 UMCG - University Medical Center Groningen [Groningen]
16 Children's Hospital of Pittsburgh of UPMC [Etats-Unis]
17 Belfast City Hospital
18 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
19 Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré]
20 HudsonAlpha Institute for Biotechnology [Huntsville, AL]
21 CRS - Children’s Rehabilitation Service [Mobile, AL]
22 University Medical Center [Utrecht]
23 CUH - Cambridge University Hospitals - NHS
24 University Hospital Leipzig
25 Donders Institute for Brain, Cognition and Behaviour
26 MUMC - Maastricht University Medical Centre
27 Cedars-Sinai Medical Center
28 CHU Montpellier

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.

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

Domains: Neuroscience

Scott Bell, Justine Rousseau, Huashan Peng, Zahia Aouabed, Pierre Priam, et al.. Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons. American Journal of Human Genetics, 2019, 104 (5), pp.815-834. ⟨10.1016/j.ajhg.2019.03.022⟩. ⟨pasteur-03325419⟩