TUFM – Combined Oxidative Phosphorylation Deficiency 4

The mitochondrial translation elongation factor Tu (TUFM) is a GTPase that delivers aminoacyl-tRNAs to the mitochondrial ribosome and is essential for oxidative phosphorylation. Bi‐allelic pathogenic variants in TUFM cause combined oxidative phosphorylation deficiency type 4 (Combined Oxidative Phosphorylation Deficiency 4), a severe autosomal recessive metabolic encephalomyopathy.

Patients typically present in infancy with lactic acidosis (HP:0003128), progressive encephalopathy (HP:0001298), hypotonia (HP:0001252), and cardiomyopathy (HP:0001638). Secondary features such as decreased liver function (HP:0001410) and optic atrophy (HP:0000648) are also reported. The phenotypic spectrum has recently expanded to include isolated cardiomyopathy without fatal encephalopathy in one patient ([PMID:30903008]).

To date, six unrelated probands with homozygous missense variants have been described, all in consanguineous families, confirming autosomal recessive inheritance ([PMID:30903008], [PMID:38630895]). Two missense alleles have been reported: c.344A>C (p.His115Pro) ([PMID:30903008]) and c.1016G>A (p.Arg339Gln) ([PMID:38630895]). No protein‐truncating or deep‐intronic variants have been observed, and no recurrent or founder alleles have been identified.

Segregation analysis is limited to parental carrier testing in consanguineous pedigrees; no extended segregation studies are available. Nonetheless, homozygosity mapping and parental heterozygosity confirm variant pathogenicity in all reported families.

Functional studies in patient fibroblasts and yeast models demonstrate that missense variants impair TUFM binding to aminoacyl‐tRNAs, abolish mitochondrial protein synthesis, and reduce complex I and IV activities ([PMID:28132884]). Molecular modeling predicts destabilization of the GTPase domain, consistent with loss of function.

No studies have disputed the TUFM–COXPD4 association. The combination of multiple unrelated probands, consistent autosomal recessive inheritance, and concordant functional data supports a strong gene–disease relationship.

Key Take-home: Biallelic missense variants in TUFM disrupt mitochondrial translation elongation, leading to combined oxidative phosphorylation deficiency 4. TUFM sequencing should be included in diagnostic panels for early‐onset lactic acidosis, cardiomyopathy, and encephalopathy.

References

• Journal of human genetics • 2019 • A novel TUFM homozygous variant in a child with mitochondrial cardiomyopathy expands the phenotype of combined oxidative phosphorylation deficiency 4 PMID:30903008
• Journal of pediatric endocrinology & metabolism : JPEM • 2024 • A very rare presentation of mitochondrial elongation factor Tu deficiency-TUFM mutation and literature review PMID:38630895
• Biochimica et biophysica acta. Molecular basis of disease • 2017 • Novel mutation in mitochondrial Elongation Factor EF-Tu associated to dysplastic leukoencephalopathy and defective mitochondrial DNA translation PMID:28132884

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