Disruption of the methyltransferase-like 23 gene METTL23 causes mild autosomal recessive intellectual disability

Abstract

We describe the characterization of a gene for mild nonsyndromic autosomal recessive intellectual disability (ID) in two unrelated families, one from Austria, the other from Pakistan. Genome-wide single nucleotide polymorphism microarray analysis enabled us to define a region of homozygosity by descent on chromosome 17q25. Whole-exome sequencing and analysis of this region in an affected individual from the Austrian family identified a 5 bp frameshifting deletion in the METTL23 gene. By means of Sanger sequencing of METTL23, a nonsense mutation was detected in a consanguineous ID family from Pakistan for which homozygosity-by-descent mapping had identified a region on 17q25. Both changes lead to truncation of the putative METTL23 protein, which disrupts the predicted catalytic domain and alters the cellular localization. 3D-modelling of the protein indicates that METTL23 is strongly predicted to function as an S-adenosyl-methionine (SAM)-dependent methyltransferase. Expression analysis of METTL23 indicated a strong association with heat shock proteins, which suggests that these may act as a putative substrate for methylation by METTL23. A number of methyltransferases have been described recently in association with ID. Disruption of METTL23 presented here supports the importance of methylation processes for intact neuronal function and brain development.

Further delineation of METTL23‐associated intellectual disability

“…Shortly after the first report, Bernkopf et al presented six additional individuals from two families who presented with milder degrees of ID and no dysmorphic features (Bernkopf et al, ). The first family was found to have a homozygous frameshift variant (c.281_285delAAGAT; p.Gln94Hisfs*6) and the other had a nonsense homozygous variant (c.397C>T; p.Gln133*).…”

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).…”

Protein lysine methylation contributes to modulating the response of sensitive and tolerant Arabidopsis species to cadmium stress

“…Its ortholog in animal cells is METTL23 (Figure S5). METTL23 is located in the cytoplasm and the nucleus, interacts with a subunit of the GA‐binding protein transcription factor, but its target(s) has not been yet identified (Bernkopf et al, ; Reiff et al, ). The profiling of methylproteins in sbs2 and Col‐0 by western blot was not sensitive enough to detect any change between the two lines (Figure S7), providing no clues to the nature of the substrate(s) of the SBS2 enzyme.…”