A missense variant impairing TRMT1 function in tRNA modification is linked to intellectual disability

Abstract

The human TRMT1 gene encodes a tRNA methyltransferase enzyme responsible for the formation of the dimethylguanosine (m2,2G) modification in cytoplasmic and mitochondrial tRNAs. 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. Moreover, the impact of ID-associated TRMT1 mutations on m2,2G levels in IDaffected patients is unknown. 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 TRMT1associated ID disorders.

Hypomodified tRNA in evolutionarily distant yeasts can trigger rapid tRNA decay to activate the general amino acid control response, but with different consequences

“…Similarly, human neurological disorders are linked to mutations in TRMT10A, associated with reduced 1-methylguanosine at G9 (m 1 G9) (23,24), TRMT1 (m 2,2 G26) (25)(26)(27)(28), WDR4 (m 7 G46) (29)(30)(31) and NSUN2, associated with reduced 5-methylcytidine (m 5 C) at C48-50, as well as at C34 and C40 (32)(33)(34).…”