Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability

J Clin Invest. 2020 Mar 2;130(3):1431-1445. doi: 10.1172/JCI131145.

Lin Li ¹, Mohammad Ghorbani ¹, Monika Weisz-Hubshman ² ³ ⁴, Justine Rousseau ⁵, Isabelle Thiffault ⁶ ⁷, Rhonda E Schnur ⁸ ⁹, Catherine Breen ¹⁰, Renske Oegema ¹¹, Marjan Mm Weiss ¹², Quinten Waisfisz ¹², Sara Welner ¹³, Helen Kingston ¹⁰, Jordan A Hills ¹⁴, Elles Mj Boon ¹², Lina Basel-Salmon ² ³ ⁴ ¹⁵, Osnat Konen ⁴ ¹⁶, Hadassa Goldberg-Stern ⁴ ¹⁷, Lily Bazak ³ ⁴, Shay Tzur ¹⁸ ¹⁹, Jianliang Jin ¹ ²⁰, Xiuli Bi ¹, Michael Bruccoleri ¹, Kirsty McWalter ⁹, Megan T Cho ⁹, Maria Scarano ⁸, G Bradley Schaefer ¹⁴, Susan S Brooks ¹³, Susan Starling Hughes ⁶ ⁷, K L I van Gassen ¹¹, Johanna M van Hagen ¹², Tej K Pandita ²¹, Pankaj B Agrawal ²², Philippe M Campeau ⁵, Xiang-Jiao Yang ¹ ²³

Affiliations

1 Rosalind and Morris Goodman Cancer Research Centre and Department of Medicine, McGill University, Montreal, Quebec, Canada.
2 Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
3 Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel.
4 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
5 Paediatric Department, CHU Sainte-Justine Hospital, University of Montreal, Quebec, Canada.
6 Center for Pediatric Genomic Medicine & Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, Missouri, USA.
7 Faculty of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
8 Division of Genetics, Cooper University Health Care, Camden, New Jersey, USA.
9 GeneDx, Gaithersburg, Maryland, USA.
10 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Manchester, United Kingdom.
11 Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands.
12 Department of Clinical Genetics, Amsterdam University Medical Center, Amsterdam, Netherlands.
13 Division of Pediatric Medical Genetics, The State University of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
14 University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
15 Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva, Israel.
16 Imaging Department, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
17 Epilepsy Unit and EEG Laboratory, Schneider Medical Center, Petach Tikva, Israel.
18 Laboratory of Molecular Medicine, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
19 Genomic Research Department, Emedgene Technologies, Tel Aviv, Israel.
20 Research Center for Bone and Stem Cells, Department of Human Anatomy, Key Laboratory of Aging & Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
21 Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas, USA.
22 Divisions of Newborn Medicine and Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
23 Departments of Biochemistry and Medicine, McGill University Health Center, Montreal, Quebec, Canada.

PMID: 31794431 DOI: 10.1172/JCI131145

Abstract

Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here, we report that cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development. Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive Apoptosis, and scant H4K16 propionylation. Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation. Moreover, we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies. The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation. Valproate was effective for treating epilepsy in at least 2 of the individuals. This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies.

Keywords

Epigenetics; Neuroscience.

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