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TRIT1 encodes human tRNA isopentenyltransferase responsible for N6-isopentenyladenosine (i6A37) modification of anticodon loops in select cytosolic and mitochondrial tRNAs. Biallelic pathogenic variants in TRIT1 cause autosomal recessive mitochondrial disease with early-onset combined oxidative phosphorylation deficiency, microcephaly, developmental delay and epilepsy. To date, 10 probands across 6 unrelated families have been reported with homozygous or compound heterozygous TRIT1 variants (10 probands: [PMID:24901367], [PMID:28185376], [PMID:32948376], [PMID:36049610], [PMID:35418828]). Affected individuals present in infancy or early childhood with global developmental delay, refractory seizures and biochemical evidence of mitochondrial respiratory chain dysfunction.
The initial report described a homozygous missense variant c.968G>A (p.Arg323Gln) in a single patient with severe combined mitochondrial respiratory chain defects ([PMID:24901367]). Subsequent matchmaking studies identified four individuals from three additional unrelated families harboring truncating variants (e.g., c.58C>T (p.Gln20Ter)) and missense alterations in TRIT1 ([PMID:28185376]). Two Korean siblings with COXPD35 exhibited a compound heterozygous c.979G>A (p.Glu327Lys) and c.682+2T>C splice-site variant ([PMID:32948376]). Two further patients carried novel missense changes such as c.246G>C (p.Met82Ile) and c.1225G>A (p.Glu409Lys), and a single case was reported with c.246G>T (p.Met82Ile) ([PMID:36049610], [PMID:35418828]).
The TRIT1 variant spectrum comprises at least 4 missense substitutions (p.Arg323Gln, p.Lys286Glu, p.Glu409Lys, p.Met82Ile) and 6 loss-of-function alleles (nonsense and frameshift). Recurrent variants cluster within an arginine-rich tRNA-binding region adjacent to the catalytic domain. No common founder alleles have been described, and carrier frequencies remain undefined.
Functional studies demonstrate severe deficiency of i6A37 modification in patient fibroblasts and reduced enzymatic activity of recombinant human TRIT1^R323Q in vitro ([PMID:24901367], [PMID:34768885]). Wild-type TRIT1 complementation fully rescues tRNA modification defects in patient cells. Conditional Trit1 knockout mouse models reveal impaired selenoprotein translation and codon-specific translational fidelity defects consistent with human biochemical and neurological phenotypes.
No reports have refuted the association or identified asymptomatic individuals with biallelic TRIT1 variants. The phenotype is highly concordant across ethnically diverse cohorts, with core features of mitochondrial respiratory chain deficiency, microcephaly, developmental delay and epilepsy.
Collectively, the genetic segregation in multiple families and robust functional concordance support a Strong gene–disease relationship. TRIT1 should be included in diagnostic panels for mitochondrial disorders. Key Take-home: Biallelic TRIT1 variants impair i6A37 tRNA modification, causing an autosomal recessive mitochondrial disease with combined oxidative phosphorylation deficiency.
Gene–Disease AssociationStrong10 probands across 6 unrelated families, biallelic segregation, functional concordance Genetic EvidenceStrongBiallelic variants in 10 individuals from 6 unrelated families including homozygous and compound heterozygous missense and loss-of-function alleles Functional EvidenceModerateStructural modelling, in vitro assays, patient fibroblast complementation and mouse models demonstrate loss of tRNA i6A37 modification |