PT  - JOURNAL ARTICLE
AU  - Jillian Ramos
AU  - Lu Han
AU  - Yan Li
AU  - Fowzan S. Alkuraya
AU  - Eric M. Phizicky
AU  - Dragony Fu
TI  - Formation of tRNA wobble inosine in humans is perturbed by a millennia-old mutation linked to intellectual disability
AID  - 10.1101/277079
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 277079
4099  - http://biorxiv.org/content/early/2018/03/07/277079.short
4100  - http://biorxiv.org/content/early/2018/03/07/277079.full
AB  - The formation of inosine at the wobble position of eukaryotic tRNAs is an essential modification catalyzed by the ADAT2/ADAT3 complex. In humans, a valine to methionine mutation (V144M) in ADAT3 that originated ∼1,600 years ago is the most common cause of autosomal-recessive intellectual disability (ID) in Arabia. Here, we show that ADAT3-V144M exhibits perturbations in subcellular localization and has increased propensity to form aggregates associated with cytoplasmic chaperonins. While ADAT2 co-expression can suppress the aggregation of ADAT3-V144M, the ADAT2/3 complexes assembled with ADAT3-V144M exhibit defects in adenosine deaminase activity. Moreover, extracts from cell lines derived from ID-affected individuals expressing only ADAT3-V144M display a reduction in tRNA deaminase activity. Notably, we find that the same cell lines from ID-affected individuals exhibit decreased wobble inosine in certain tRNAs. These results identify a role for ADAT2-dependent localization and folding of ADAT3 in wobble inosine modification that is crucial for the developing human brain.