Talk abstracts
Talk on Saturday 01:15-01:30pm submitted by Kejia Zhang
A missense variant impairing TRMT1 function in tRNA modification is linked to intellectual disability
Kejia Zhang (Department of Biology, Center for RNA Biology, University of Rochester), Dragony Fu (Department of Biology, Center for RNA Biology, University of Rochester)
Abstract:
Transfer RNAs (tRNAs) are subject to numerous post-transcriptional modifications. In mammalian cells, tRNA methyltransferase 1 (TRMT1) is a tRNA methyltransferases that catalyzes the formation of the dimethylguanosine (m2,2G) modification in more than half of tRNA species. Frameshift mutations in the TRMT1 gene have been shown to cause autosomal-recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Here, we describe a homozygous missense variant in TRMT1 in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes a conserved arginine residue to a cysteine (R323C) within the methyltransferase domain of TRMT1 and is expected to perturb protein folding. Patient cells expressing the TRMT1-R323C variant exhibit a severe deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss-of-function. Notably, the TRMT1 R323C mutant retains the ability to bind tRNA but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that severely perturbs tRNA modification activity, and provide the first demonstration that m2,2G modifications are disrupted in patients with TRMT1-associated ID disorders. These findings underscore the key relationship between human neurodevelopment and tRNA modifications.
References:
Dewe, J. M., Fuller, B. L., Lentini, J. M., Kellner, S. M., & Fu, D. (2017). TRMT1-Catalyzed tRNA Modifications Are Required for Redox Homeostasis To Ensure Proper Cellular Proliferation and Oxidative Stress Survival. Mol Cell Biol, 37(21).doi:10.1128/MCB.00214-17
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S., Chen, W.,... Ropers, H. (2011).Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature, 478(7367), 57-63. doi:10.1038/nature10423
Keywords: tRNA modification, TRMT1, neurodevelopment