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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • DNA Modification Methylases / genetics
  • DNA Modification Methylases / metabolism*
  • Female
  • GA-Binding Protein Transcription Factor / genetics
  • GA-Binding Protein Transcription Factor / metabolism*
  • Genotype
  • Humans
  • Immunoprecipitation
  • Male
  • Mitochondrial Proton-Translocating ATPases / genetics
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Polymorphism, Single Nucleotide / genetics
  • Protein Binding
  • RNA, Small Interfering
  • Thrombopoietin / genetics
  • Thrombopoietin / metabolism
  • Two-Hybrid System Techniques


  • ATP5F1B protein, human
  • GA-Binding Protein Transcription Factor
  • GABPA protein, human
  • RNA, Small Interfering
  • Thrombopoietin
  • DNA Modification Methylases
  • Mitochondrial Proton-Translocating ATPases