Molecular characteristics
The TRMT1 (tRNA methyltransferase 1) gene is located at 19p13.3 and encodes tRNA methyltransferase-1 which is responsible for catalysing dimethylguanosine (m2,2G) formation in tRNA using the substrate S-adenosyl-L-methionine.
Mutations and pathophysiology
Frameshift and missense pathogenic variants in TRMT1 have been shown to cause MRT68, which is characterized mainly by intellectual disability, developmental delay, and mild facial dysmorphism.
The following are two selected examples of pathogenic variants in TRMT1:
Zhang et al. (2019) reported homozygosity for c.967C>T missense variant in TRMT1 (NM_001136035.3) leading to a p.Arg323Cys substitution. The affected patient was an 8-year-old female with intellectual disability, delayed cognitive development, generalized epilepsy, and mild dysmorphic features in the form of deep-set eyes, epicanthus, smooth philtrum, and pointed chin.
Judith Rapoport (personal communication) reported a compound heterozygous mutation in TRMT1: NM_001136035.3: c.1332_1333delGT (p.Tyr445LeufsTer28); c.232C>T (p.Gln78Ter). The patient is a 3.5-year-old boy who was found to have MRT68 with the following signs and symptoms:
- Hypotonia
- Global developmental delay (with a motor DQ of 48)
- Verbal dyspraxia (with a verbal DQ of 45)
- Breath-holding spells
- Joint hyperlaxity
- Persistent fetal fingertip pads
- Hearing impairment
- Fifth finger clinodactyly
- Strabismus
- Thrombocytosis
The patient is currently treated with speech therapy, VML method, and equine-assisted therapy.
Blaesius et al. (2018) reported a frameshift and premature termination (p.Q219H fs*22) in the methyltransferase domain resulting from a c.657_688del32 in TRMT1 (NM_001136035). The patient was born to a consanguineous Pakistani family and presented with mild to moderate intellectual disability, microcephaly that was diagnosed at birth, developmental delay, muscle weakness, and generalized epilepsy.