Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual Disability and Microcephaly

Abstract

Intellectual disability (ID) is a genetically and clinically heterogeneous disorder, characterized by limited cognitive abilities and impaired adaptive behaviors. In recent years, exome sequencing (ES) has been instrumental in deciphering the genetic etiology of ID. Here, through ES of a large cohort of individuals with ID, we identified two bi-allelic frameshift variants in METTL5, c.344_345delGA (p.Arg115Asnfs*19) and c.571_572delAA (p.Lys191Valfs*10), in families of Pakistani and Yemenite origin. Both of these variants were segregating with moderate to severe ID, microcephaly, and various facial dysmorphisms, in an autosomal-recessive fashion. METTL5 is a member of the methyltransferase-like protein family, which encompasses proteins with a seven-beta-strand methyltransferase domain. We found METTL5 expression in various substructures of rodent and human brains and METTL5 protein to be enriched in the nucleus and synapses of the hippocampal neurons. Functional studies of these truncating variants in transiently transfected orthologous cells and cultured hippocampal rat neurons revealed no effect on the localization of METTL5 but alter its level of expression. Our in silico analysis and 3D modeling simulation predict disruption of METTL5 function by both variants. Finally, mettl5 knockdown in zebrafish resulted in microcephaly, recapitulating the human phenotype. This study provides evidence that biallelic variants in METTL5 cause ID and microcephaly in humans and highlights the essential role of METTL5 in brain development and neuronal function.

The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs

“…While our manuscript was under revision, a METTL5 morpholino zebrafish model was described that recapitulated the human microcephaly phenotype ( Fig. 5G; Richard et al 2019). In mice, alveolar bone loss upon Mettl5 mutations has been described (Sima et al 2016).…”

Further delineation of METTL23‐associated intellectual disability

“…The function of many of METTL proteins is still not fully characterized (Ignatova, Jansen, Baltissen, Vermeulen, & Schneider, 2019). Very recently, METTL5 was found to be associated with autosomal recessive intellectual disability and microcephaly (Richard et al, 2019).…”

The role of m6A modification in physiology and disease

“…These results reveal that m 6 A methylation serves a crucial role in normal physiology and in responses to pathological stimuli in the adult mammalian nervous system 89 . METTL5 is abundant in the nucleus and synapses of hippocampal neurons, and its deletion leads to microcephaly in zebrafish 90 .…”

“… Molecule Molecular functions Localization Disease and mechanism Neuronal disorders METTL14/YTHDF1 Translation activation DRG neurons Facilitates axon regeneration of adult DRG neurons by promoting injury-induced protein synthesis 89 . METTL5 Unknown Hippocampal neurons Its deletion causes microcephaly in zebrafish 90 . FTO/ALKBH5 Unknown Not sure Major depression 91 – 93 .…”