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

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Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2019-04-25 , DOI: 10.1016/j.ajhg.2019.03.022
Scott Bell ₁ , Justine Rousseau ₂ , Huashan Peng ₁ , Zahia Aouabed ₁ , Pierre Priam ₃ , 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 ₄ , Jessica Sebastian ₄ , Jerry Vockley ₄ , Amber G Begtrup ₅ , Ingrid M Wentzensen ₅ , Amy Crunk ₅ , Robert D Nicholls ₄ , Kristin C Herman ₆ , Joshua L Deignan ₇ , Walla Al-Hertani ₈ , Stephanie Efthymiou ₉ , Vincenzo Salpietro ₉ , Noriko Miyake ₁₀ , Yoshio Makita ₁₁ , Naomichi Matsumoto ₁₀ , Rune Østern ₁₂ , Gunnar Houge ₁₃ , Maria Hafström ₁₂ , Emily Fassi ₁₄ , Henry Houlden ₉ , Jolien S Klein Wassink-Ruiter ₁₅ , Dominic Nelson ₁₆ , Amy Goldstein ₁₇ , Tabib Dabir ₁₈ , Julien van Gils ₁₉ , Thomas Bourgeron ₁₉ , Richard Delorme ₂₀ , Gregory M Cooper ₂₁ , Jose E Martinez ₂₂ , Candice R Finnila ₂₁ , Lionel Carmant ₂₂ , Anne Lortie ₂₃ , Renske Oegema ₂₄ , Koen van Gassen ₂₄ , Sarju G Mehta ₂₅ , Dagmar Huhle ₂₅ , Rami Abou Jamra ₂₆ , Sonja Martin ₂₆ , Han G Brunner ₂₇ , Dick Lindhout ₂₈ , Margaret Au ₂₉ , John M Graham ₂₉ , Christine Coubes ₃₀ , Gustavo Turecki ₁ , Simon Gravel ₁₅ , Naguib Mechawar ₁ , Elsa Rossignol ₂ , Jacques L Michaud ₂ , Julie Lessard ₃ , Carl Ernst ₁ , Philippe M Campeau ₂

Affiliation

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.

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.

中文翻译：

ACTL6B 突变会导致神经发育缺陷和癫痫，并导致人类神经元树突丢失。

我们确定了 ACTL6B 存在变异的个体，ACTL6B 是包括 BAF 复合体在内的染色质重塑机制的一个组成部分。10 名个体携带双等位基因突变，并出现全面发育迟缓、癫痫性脑病和痉挛，10 名携带新杂合突变的个体表现出智力障碍、行走缺陷、严重语言障碍、肌张力低下、雷特样刻板印象和轻微面部畸形（宽嘴、纵裂、球鼻）。这 10 个不相关的个体中有 9 个具有相同的从头 c.1027G>A (p.Gly343Arg) 突变。生成的人源神经元重新捕获了从祖细胞到有丝分裂后神经元发育过程中的 ACTL6B 表达模式，验证了该模型的使用。在野生型人类神经元中工程敲除 ACTL6B 会导致树突发育严重缺陷，这一结果在具有不同双等位基因突变的两个个体中得到重演，并在克隆基因修复或 ACTL6B 的外源表达上逆转。对野生型和双等位突变 ACTL6B 神经祖细胞和神经元中 BAF 复合物的全转录组分析和全基因组分析表明，ACTL6B 突变体中 BAF 复合物的基因组结合增加，包括 TPPP 和FSCN1，表明某些细胞骨架基因的调节改变导致树突发育改变。在 ACTL6B 敲除人类背景上对双等位基因和杂合 ACTL6B 突变的评估表明，双等位基因突变模拟工程缺失缺陷，而杂合突变则不然，这表明前者是功能丧失，后者是功能获得。这些结果揭示了 ACTL6B 在神经发育中的作用，并暗示了大脑疾病中染色质重塑机制的另一个组成部分。

更新日期：2019-05-16

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