An intellectual disability-associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity.
Hum Mutat
; 41(3): 600-607, 2020 03.
Article
em En
| MEDLINE
| ID: mdl-31898845
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
TRNA Metiltransferases
/
RNA de Transferência
/
Mutação de Sentido Incorreto
/
Deficiência Intelectual
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Female
/
Humans
Idioma:
En
Revista:
Hum Mutat
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2020
Tipo de documento:
Article