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

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.

Further delineation of METTL23‐associated intellectual disability

“…In 2014, Reiff et al described a consanguineous family of Arab origin with seven members affected with ID and mild dysmorphic features. They identified a frameshift homozygous variant (c.169_172delCACT; p.His57Valfs*11) in affected members (Reiff et al, ). In that report, Reiff et al showed that METTL23 is expressed at low‐to‐moderate levels in the developing human brain, localizing to both the cytoplasm and the nucleus (Reiff et al, ).…”

“…They identified a frameshift homozygous variant (c.169_172delCACT; p.His57Valfs*11) in affected members (Reiff et al, ). In that report, Reiff et al showed that METTL23 is expressed at low‐to‐moderate levels in the developing human brain, localizing to both the cytoplasm and the nucleus (Reiff et al, ). They showed that METTL23 interacts with the alpha subunit of transcription factor subunit GABP (GA‐binding protein) and this complex regulates the expression of crucial target genes.…”

Identification and Characterization of a Novel Evolutionarily Conserved Lysine-specific Methyltransferase Targeting Eukaryotic Translation Elongation Factor 2 (eEF2)

“…In mice, however, the loss of single DPH genes leads to abnormal embryonic development and even lethality (43,44). No studies have reported any phenotypes or genetic disorders associated with eEF2-KMT inactivation, but it was recently reported that inactivation of another, yet uncharacterized, human MTF16 member, METTL23, caused intellectual disability (45,46).…”

Asparagine synthetase deficiency detected by whole exome sequencing causes congenital microcephaly, epileptic encephalopathy and psychomotor delay

“…Furthermore, it has been shown that the loss of the ASNS function results in accumulation of aspartate and glutamate in the brain leading to in increased excitability, seizure activity, and neuronal damage (Ruzzo et al 2013). The discovery of pathogenic mutations is important for adopting effective prevention and therapeutic approaches that might minimize the burden of genetic conditions particularly in Arab population (Al-Gazali and Ali 2010; Schuurs-Hoeijmakers et al 2012; Akawi et al 2013; Reiff et al 2014). …”