TY - JOUR
T1 - METTL23, a transcriptional partner of GABPA, is essential for human cognition
AU - Reiff, Rachel E.
AU - Ali, Bassam R.
AU - Baron, Byron
AU - Yu, Timothy W.
AU - Ben-Salem, Salma
AU - Coulter, Michael E.
AU - Schubert, Christian R.
AU - Sean Hill, R.
AU - Akawi, Nadia A.
AU - Al-Younes, Banan
AU - Kaya, Namik
AU - Evrony, Gilad D.
AU - Al-Saffar, Muna
AU - Felie, Jillian M.
AU - Partlow, Jennifer N.
AU - Sunu, Christine M.
AU - Schembri-Wismayer, Pierre
AU - Alkuraya, Fowzan S.
AU - Meyer, Brian F.
AU - Walsh, Christopher A.
AU - Al-Gazali, Lihadh
AU - Mochida, Ganeshwaran H.
N1 - Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke (2R01NS035129 to C.A.W.); the National Institute of Mental Health (R01MH083565 to C.A.W.); the Fogarty International Center (R21TW008223 to C.A.W.) and also by the Simons Foundation, the Dubai Harvard Foundation for Medical Research and the Manton Center for Orphan Disease Research. R.E.R. and G.D.E. were supported by award T32GM007753 from the National Institute of General Medical Sciences. T.W.Y. was supported by the National Institutes of Health (T32NS007484-08), the Clinical Investigator Training Program at Harvard-MIT Health Sciences and Technology and Beth Israel Deaconess Medical Center in collaboration with Pfizer, Inc. and Merck & Co., Inc. and the Nancy Lurie Marks Junior Faculty MeRIT Fellowship. M.E.C. was supported by award 1F30MH702909-01 from the National Institute of Mental Health.
Funding Information:
We thank the individuals and their families reported herein for their participation in this research. SNP genotyping of the UAE branch was performed at the W.M. Keck Foundation Biotechnology Resource Laboratory at Yale University through the National Institutes of Health Neuroscience Microarray Consortium. SNP genotyping of the KSA branch was performed at the Genotyping Core Facility laboratory at the King Faisal Specialist Hospital and Research Centre. Human embryonic material was provided by the joint MRC/Wellcome Trust (grant 099175/Z/ 12/Z) Human Developmental Biology Resource (www. HDBR.org). C.A.W. is an Investigator of the Howard Hughes Medical Institute. The content of this project is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health.
PY - 2014/7
Y1 - 2014/7
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddu054
DO - 10.1093/hmg/ddu054
M3 - Article
C2 - 24501276
AN - SCOPUS:84902342545
SN - 0964-6906
VL - 23
SP - 3456
EP - 3466
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 13
M1 - ddu054
ER -