COX4I1 – cytochrome-c oxidase deficiency disease

COX4I1 encodes the canonical subunit 4 isoform of cytochrome c oxidase (complex IV) in the mitochondrial respiratory chain. Autosomal recessive pathogenic variants in COX4I1 result in primary cytochrome-c oxidase deficiency with heterogeneous phenotypes. A homozygous c.303G>T (p.Lys101Asn) variant was identified in a child presenting with short stature, failure to thrive, dysmorphic features, and Fanconi anemia-like bone marrow failure (PMID:28766551). A compound heterozygous 16q24.1 deletion and c.454C>A (p.Pro152Thr) variant was found in a 6-year-old boy with developmental regression, epilepsy, microcephaly, hypotonia, and progressive cerebral atrophy (PMID:40095452). Both variants segregated with disease consistent with autosomal recessive inheritance. In total, two unrelated probands have been described, providing initial but limited genetic support for the gene–disease association.

Functional studies in patient fibroblasts carrying the p.Lys101Asn variant demonstrated markedly reduced COX activity, impaired ATP synthesis, elevated ROS, and decreased COX4I1 expression, all of which were rescued by lentiviral delivery of wild-type COX4I1 (PMID:28766551). Further investigations revealed replicative stress and an impaired nuclear DNA damage response in COX4I1-deficient cells, linking mitochondrial dysfunction to genomic instability (PMID:35456968). Upregulation of the hypoxia-inducible COX4-2 isoform via HIF-1α stabilization has also been observed as a compensatory response in COX4I1 deficiency (PMID:33672589). These data establish a loss-of-function mechanism for COX4I1-related disease and demonstrate concordant molecular and cellular phenotypes. Based on two probands with familial segregation and consistent functional concordance, the clinical validity meets a Limited classification with Moderate functional evidence support. Key take-home: COX4I1 sequencing should be considered in patients with unexplained complex IV deficiency presenting with neurologic, hematologic, or multisystem manifestations.

References

• European journal of human genetics • 2017 • Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia. PMID:28766551
• Epilepsia open • 2025 • Compound heterozygosity of a De novo 16q24.1 deletion and missense mutation in COX4I1 leads to developmental regression, intellectual disability, and seizures. PMID:40095452
• International journal of molecular sciences • 2022 • Replicative Stress Coincides with Impaired Nuclear DNA Damage Response in COX4-1 Deficiency. PMID:35456968
• Cells • 2021 • Upregulation of COX4-2 via HIF-1α in Mitochondrial COX4-1 Deficiency. PMID:33672589

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