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Hum Mol Genet. 2014 Jul 1;23(13):3456-66. doi: 10.1093/hmg/ddu054. Epub 2014 Feb 5.

METTL23, a transcriptional partner of GABPA, is essential for human cognition.

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  • 1Division of Genetics and Genomics, Department of Medicine Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA Harvard-Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
  • 2Department of Pathology, College of Medicine and Health Sciences.
  • 3Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, Msida MSD2080, Malta.
  • 4Division of Genetics and Genomics, Department of Medicine Department of Pediatrics Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
  • 5Division of Genetics and Genomics, Department of Medicine Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA Department of Pediatrics Research Laboratory of Electronics and Department of Electrical Engineering and Computer Science, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
  • 6Division of Genetics and Genomics, Department of Medicine Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
  • 7Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • 8Division of Genetics and Genomics, Department of Medicine Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA Program in Biological and Biomedical Sciences and.
  • 9Division of Genetics and Genomics, Department of Medicine Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al-Ain, United Arab Emirates.
  • 10Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
  • 11Division of Genetics and Genomics, Department of Medicine Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA Department of Pediatrics Department of Neurology, Harvard Medical School, Boston, MA 02115, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
  • 12Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al-Ain, United Arab Emirates.
  • 13Division of Genetics and Genomics, Department of Medicine Manton Center for Orphan Disease Research and Department of Pediatrics Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA ganesh.mochida@childrens.harvard.edu.

Abstract

Whereas many genes associated with intellectual disability (ID) encode synaptic proteins, transcriptional defects leading to ID are less well understood. We studied a large, consanguineous pedigree of Arab origin with seven members affected with ID and mild dysmorphic features. Homozygosity mapping and linkage analysis identified a candidate region on chromosome 17 with a maximum multipoint logarithm of odds score of 6.01. Targeted high-throughput sequencing of the exons in the candidate region identified a homozygous 4-bp deletion (c.169_172delCACT) in the METTL23 (methyltransferase like 23) gene, which is predicted to result in a frameshift and premature truncation (p.His57Valfs*11). Overexpressed METTL23 protein localized to both nucleus and cytoplasm, and physically interacted with GABPA (GA-binding protein transcription factor, alpha subunit). GABP, of which GABPA is a component, is known to regulate the expression of genes such as THPO (thrombopoietin) and ATP5B (ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide) and is implicated in a wide variety of important cellular functions. Overexpression of METTL23 resulted in increased transcriptional activity at the THPO promoter, whereas knockdown of METTL23 with siRNA resulted in decreased expression of ATP5B, thus revealing the importance of METTL23 as a regulator of GABPA function. The METTL23 mutation highlights a new transcriptional pathway underlying human intellectual function.

© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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