GTPBP3 and Combined Oxidative Phosphorylation Deficiency 23

The association between GTPBP3 and Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) is supported by multiple independent lines of evidence from case reports, patient series, and functional studies. The current data consistently show that biallelic variants in GTPBP3 are causative for this rare mitochondrial disorder. Clinical reports describe patients with a broad spectrum of symptoms, including intellectual disability, motor delay, hypertrophic cardiomyopathy, seizures, feeding difficulties, gait abnormalities, and lactic acidosis (PMID:36980825, PMID:34276756).

Genetic evidence for this gene‑disease association is substantial. Inheritance is autosomal recessive, and segregation studies in multiple unrelated families have demonstrated that affected individuals inherit compound heterozygous or homozygous variants in GTPBP3 (PMID:35413567). For example, one study identified a proband with one novel variant, c.1102dupC (p.Arg368ProfsTer22), inherited from one parent and a previously reported variant from the other (PMID:36980825).

Case series and curated studies have reported around 20 unique probands with various mutation types in GTPBP3 – including missense, frameshift (loss‑of‑function), and splicing variants – that co‐segregate with the COXPD23 phenotype. The spectrum of variants, enriched in functionally critical domains of the protein, strongly supports a loss‑of‑function mechanism for pathogenicity (PMID:38327089, PMID:38515655).

Functional data further corroborate the genetic findings. Experimental studies, including yeast complementation assays and in vitro GTPase activity testing, have demonstrated that GTPBP3 is crucial for mitochondrial tRNA modification. Inactivation of GTPBP3 leads to defective mitochondrial translation and respiratory chain deficiencies that mimic the patient phenotype (PMID:12370316, PMID:33619562). Additional studies also suggest that GTPBP3 may act as a modifier of phenotypic expression in mitochondrial disorders.

There is no significant conflicting evidence against this association, though one report linked GTPBP3 variants with hypertrophic cardiomyopathy in a complex genetic context (PMID:37029485). Overall, the genetic and experimental data converge to establish a strong clinical validity for the role of GTPBP3 in COXPD23.

Key Take‑home: The strong gene‑disease association, supported by robust multi‑patient genetic data and validated functional assays, underscores the critical role of GTPBP3 in the diagnostic workup and clinical management of patients with COXPD23.

References

• Stem cell research • 2022 • Generation of patient‑derived IPSC lines from a girl with Combined Oxidative Phosphorylation Deficiency 23 PMID:35413567
• Genes • 2023 • Pathogenicity Analysis of a Novel Variant in GTPBP3 Causing Mitochondrial Disease and Systematic Literature Review PMID:36980825
• Annals of Clinical and Translational Neurology • 2024 • Biallelic variants in GTPBP3: New patients, phenotypic spectrum, and outcome PMID:38327089
• Heliyon • 2024 • A novel mutation in GTPBP3 causes combined oxidative phosphorylation deficiency 23 by affecting pre‑mRNA splicing PMID:38515655
• Frontiers in Genetics • 2021 • Novel Mutations in the GTPBP3 Gene for Mitochondrial Disease and Characteristics of Related Phenotypic Spectrum: The First Three Cases From China PMID:34276756
• Molecular and Cellular Biology • 2002 • A human mitochondrial GTP binding protein related to tRNA modification may modulate phenotypic expression of the deafness‑associated mitochondrial 12S rRNA mutation PMID:12370316
• Nucleic Acids Research • 2021 • The human tRNA taurine modification enzyme GTPBP3 is an active GTPase linked to mitochondrial diseases PMID:33619562
• American Journal of Medical Genetics. Part A • 2023 • Novel insights on GTPBP3‑associated hypertrophic cardiomyopathy PMID:37029485

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