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Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth

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Abstract

The 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the HIRA (Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene associated with a neurodevelopmental disorder in two unrelated patients. HIRA is located within the commonly deleted region of the 22q11DS and encodes a histone chaperone that regulates neural progenitor proliferation and neurogenesis, and that belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. To address the specific impact of HIRA haploinsufficiency in the neurodevelopmental phenotype of 22q11DS, we combined Hira knock-down strategies in developing mouse primary hippocampal neurons, and the direct study of brains from heterozygous Hira+/− mice. Our in vitro analyses revealed that Hira gene is mostly expressed during neuritogenesis and early dendritogenesis stages in mouse total brain and in developing primary hippocampal neurons. Moreover, shRNA knock-down experiments showed that a twofold decrease of endogenous Hira expression level resulted in an impaired dendritic growth and branching in primary developing hippocampal neuronal cultures. In parallel, in vivo analyses demonstrated that Hira+/− mice displayed subtle neuroanatomical defects including a reduced size of the hippocampus, the fornix and the corpus callosum. Our results suggest that HIRA haploinsufficiency would likely contribute to the complex pathophysiology of the neurodevelopmental phenotype of 22q11DS by impairing key processes in neurogenesis and by causing neuroanatomical defects during cerebral development.

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Data availability

The data and materials used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

We would like to thank the patients and their families. We also thank the « IBiSA Electron Microscopy Facility » of the University of Tours for management and access to the confocal microscopy platform. This work was funded by the Association pour le Développement de la Neurogénétique (ADN) and The Fondation de France (to F.L.), and the Institut National de la Santé et de la Recherche Médicale (Inserm) for providing material support. The authors thank staff at the Research Support Facility (Sanger Institute) for their excellent care of the mice and the members of the genome engineering, genotyping, phenotyping and database teams for their contribution to this work.

Funding

This work was funded by the Association pour le Développement de la Neurogénétique (ADN) and The Fondation de France (to F.L.), and the Institut National de la Santé et de la Recherche Médicale (Inserm) for providing material support.

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Author notes

  1. Marie-Laure Vuillaume, Dévina C. Ung and Valerie E. Vancollie contributed equally to this work.

  2. Tjitske Kleefstra and Binnaz Yalcin contributed equally to this work.

  3. Frédéric Laumonnier and Annick Toutain contributed equally to this work.

Authors and Affiliations

  1. Service de Génétique, Centre Hospitalier Régional Universitaire, Tours, France

    Médéric Jeanne, Marie-Laure Vuillaume, Sandrine Vonwill, Damien Haye, Nora Chelloug, Marie-Pierre Moizard, Frédéric Laumonnier & Annick Toutain

  2. UMR 1253, iBrain, University of Tours, Inserm, Tours, France

    Médéric Jeanne, Marie-Laure Vuillaume, Dévina C. Ung, Sylviane Marouillat, Frédéric Laumonnier & Annick Toutain

  3. Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, Hinxton, UK

    Valerie E. Vancollie

  4. Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France

    Christel Wagner, Stephan C. Collins & Binnaz Yalcin

  5. Institut National de la Santé et de la Recherche Médicale (Inserm), U 1258, Illkirch, France

    Christel Wagner, Stephan C. Collins & Binnaz Yalcin

  6. Université de Strasbourg, Illkirch, France

    Christel Wagner, Stephan C. Collins & Binnaz Yalcin

  7. Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands

    Rolph Pfundt, Joost Kummeling & Tjitske Kleefstra

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  1. Médéric Jeanne
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Contributions

MJ, FL, BY, and AT contributed to the study conception and design. Clinical and genetic data collection and analysis were performed by MJ, M-LV, SW, DH, NC, RP, JK, M-PM, TK and AT. Material preparation, in vitro and in vivo functional experiments and analyses were performed by MJ, DCU, VEV, CW, SC, SM, BY and FL. The first draft of the manuscript was written by MJ, M-LV, BY, FL and AT, and all authors commented on previous versions of the manuscript. All authors have reviewed and approved the finalized manuscript.

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Correspondence to Frédéric Laumonnier.

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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The study was approved by the local institutional review boards, and written informed consent was obtained from the patients’ parents, including explicit permission to share clinical and identifying information. All mouse experiments performed at the University of Tours/INSERM were approved by the French Ministry of Research (Project authorization number 01456.03). The care and use of Hira± mice in the Wellcome Sanger Institute study was carried out in accordance with UK Home Office regulations, UK Animals (Scientific Procedures) Act of 1986 under two UK Home Office licences (80/2485 and P77453634) that approved this work, which were reviewed regularly by the Wellcome Sanger Institute Animal Welfare and Ethical Review Body.

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The study was approved by the local institutional review boards, and written informed consent was obtained from the patients’ parents, including explicit permission to share clinical and identifying information.

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The study was approved by the local institutional review boards, and written informed consent was obtained from the patients’ parents, including explicit permission to share clinical and identifying information.

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Jeanne, M., Vuillaume, ML., Ung, D.C. et al. Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth. Hum Genet 140, 885–896 (2021). https://doi.org/10.1007/s00439-020-02252-1

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