TRIT1 – Combined Oxidative Phosphorylation Deficiency 35

TRIT1 (Gene Symbol) encodes a mitochondrial tRNA isopentenyltransferase essential for i6A37 modification of cytosolic and mitochondrial tRNAs. Bi-allelic loss-of-function or missense mutations in TRIT1 cause autosomal recessive Combined Oxidative Phosphorylation Deficiency 35 (Disease Name), leading to impaired mitochondrial translation and multi-organ dysfunction. Affected individuals typically present in infancy with global developmental delay, microcephaly, refractory epilepsy, axial hypotonia, and failure to thrive, often accompanied by spastic tetraparesis, dysmorphic facies, ketotic hypoglycemia, strabismus, bicuspid aortic valve, and nephrolithiasis ([PMID:35418828]).

To date, 10 unrelated probands with COXPD35 harboring homozygous or compound heterozygous TRIT1 variants have been reported, spanning five publications over eight years ([PMID:24901367]; [PMID:28185376]; [PMID:32948376]; [PMID:35418828]; [PMID:36049610]). Segregation analysis across at least six affected relatives in three independent families confirms recessive inheritance and co-segregation of pathogenic alleles ([PMID:28185376]; [PMID:32948376]).

Inheritance is autosomal recessive, with both homozygous and compound heterozygous missense (e.g., c.246G>C (p.Met82Ile)), nonsense, frameshift, and splice-site variants reported in TRIT1. Founder and recurrent variants have not been described to date, consistent with an ultrarare disorder.

Functionally, patient fibroblasts bearing TRIT1 missense mutations (p.Arg323Gln, p.Met82Ile) exhibit severe deficiency of i6A37 modification in both cytosolic and mitochondrial tRNAs, resulting in impaired mitochondrial protein synthesis. Complementation with wild-type TRIT1 restores i6A37 levels and rescues translational defects ([PMID:24901367]; [PMID:28185376]). Mouse models with tissue-specific Trit1 knockout corroborate the critical role of TRIT1 in tRNA modification and mitochondrial function.

No studies to date have provided conflicting evidence for TRIT1’s role in COXPD35. The cumulative genetic and experimental data meet criteria for a Definitive gene-disease association. TRIT1 testing is clinically actionable for confirming diagnosis, guiding management, and genetic counseling in families with suspected mitochondrial translation defects.

Key Take-home: Biallelic TRIT1 mutations cause a definitive autosomal recessive COXPD35 characterized by early neurodevelopmental impairment, mitochondrial dysfunction, and systemic manifestations.

References

• PLoS genetics • 2014 • Defective i6A37 modification of mitochondrial and cytosolic tRNAs results from pathogenic mutations in TRIT1 and its substrate tRNA. PMID:24901367
• Human mutation • 2017 • Matchmaking facilitates the diagnosis of an autosomal-recessive mitochondrial disease caused by biallelic mutation of the tRNA isopentenyltransferase (TRIT1) gene. PMID:28185376
• Brain & development • 2021 • The first Korean cases of combined oxidative phosphorylation deficiency 35 with two novel TRIT1 mutations in two siblings confirmed by clinical and molecular investigation. PMID:32948376
• Molecular syndromology • 2022 • A Case of Combined Oxidative Phosphorylation Deficiency 35 Associated with a Novel Missense Variant of the TRIT1 Gene. PMID:35418828
• European journal of medical genetics • 2022 • TRIT1 deficiency: Two novel patients with four novel variants. PMID:36049610

Evidence Based Scoring (AI generated)