An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity
| Autor: | Christopher T Prevost, M. Hashem, Jenna M. Lentini, Fowzan S. Alkuraya, Kejia Zhang, Dragony Fu |
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| Rok vydání: | 2020 |
| Předmět: |
TRNA modification
Mutant Population Mutation Missense Biology medicine.disease_cause Article Frameshift mutation Consanguinity 03 medical and health sciences RNA Transfer Intellectual Disability Genetics medicine Humans Missense mutation Amino Acid Sequence education Genetics (clinical) 030304 developmental biology tRNA Methyltransferases 0303 health sciences Mutation education.field_of_study Point mutation 030305 genetics & heredity TRNA binding Pedigree Enzyme Activation Genetic Loci Female Protein Binding |
| Zdroj: | Hum Mutat |
| ISSN: | 1098-1004 1059-7794 |
| DOI: | 10.1002/humu.23976 |
| Popis: | The human TRMT1 gene encodes an RNA methyltransferase enzyme responsible for catalyzing dimethylguanosine (m2,2G) formation in transfer RNAs (tRNAs). Frameshift mutations in TRMT1 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 TRMT1 missense variant in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes an arginine residue to a cysteine (R323C) within the methyltransferase domain and is expected to perturb protein folding. Patient cells expressing TRMT1-R323C exhibit a deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss of function. Notably, the TRMT1 R323C mutant retains tRNA binding but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that perturbs tRNA modification activity and demonstrate that m2,2G modifications are disrupted in the cells of patients with TRMT1-associated ID disorders. |
| Databáze: | OpenAIRE |
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