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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
METTL23, a transcriptional partner of GABPA, is essential for human cognition
Human Molecular Genetics, Volume 23, No. 13, Article ddu054, Year 2014
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Description
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, H1 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 withsiRNAresulted in decreased expression ofATP5B, thus revealing the importance ofMETTL23as 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.
Authors & Co-Authors
Reiff, Rachel E.
United States, Boston
Boston Children's Hospital
United States, Cambridge
Massachusetts Institute of Technology
Ali, Bassam R.
United Arab Emirates, Al Ain
College of Medicine and Health Sciences United Arab Emirates University
Baron, Byron
Malta, Msida
L-università Ta' Malta
Yu, Timothy W.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
United States, Boston
Massachusetts General Hospital
United States, Cambridge
Harvard University
Ben-Salem, Salma
United Arab Emirates, Al Ain
College of Medicine and Health Sciences United Arab Emirates University
Coulter, Michael E.
United States, Boston
Boston Children's Hospital
United States, Cambridge
Massachusetts Institute of Technology
Schubert, Christian R.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
United States, Cambridge
Harvard-mit Health Sciences and Technology
Sean Hill, R.
United States, Boston
Boston Children's Hospital
Akawi, Nadia
United Arab Emirates, Al Ain
College of Medicine and Health Sciences United Arab Emirates University
Al-Younes, Banan
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Kaya, Namik
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Evrony, Gilad D.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
Al-Saffar, Muna
United States, Boston
Boston Children's Hospital
United Arab Emirates, Al Ain
College of Medicine and Health Sciences United Arab Emirates University
Felie, Jillian M.
United States, Boston
Boston Children's Hospital
Partlow, Jennifer Neil
United States, Boston
Boston Children's Hospital
Sunu, Christine M.
United States, Boston
Boston Children's Hospital
Schembri-Wismayer, Pierre
Malta, Msida
L-università Ta' Malta
Alkuraya., Fowzan S.
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Saudi Arabia, Riyadh
College of Medicine Alfaisal University
Meyer, Brian Francis
Saudi Arabia, Riyadh
King Faisal Specialist Hospital and Research Centre
Walsh, Christopher A.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
United States, Cambridge
Harvard University
Al-Gazali, Lihadh I.
United Arab Emirates, Al Ain
College of Medicine and Health Sciences United Arab Emirates University
Mochida, Ganeshwaran H.
United States, Boston
Boston Children's Hospital
United States, Boston
Harvard Medical School
United States, Boston
Massachusetts General Hospital
Statistics
Citations: 41
Authors: 22
Affiliations: 10
Identifiers
Doi:
10.1093/hmg/ddu054
ISSN:
09646906
e-ISSN:
14602083
Research Areas
Cancer
Disability
Genetics And Genomics
Maternal And Child Health