FOXRED1 – Mitochondrial Complex I Deficiency

This summary integrates evidence linking FOXRED1 variants to mitochondrial complex I deficiency. Multiple independent studies have identified patients harboring biallelic (autosomal recessive) variants in FOXRED1, with consistent clinical presentations that include ataxia, seizures, global developmental delay, and congenital lactic acidosis (PMID:31434271, PMID:30723688). The combined clinical and experimental data across these studies provide a robust framework supporting FOXRED1 as a key gene in the pathogenesis of this mitochondrial disorder.

Genetic evidence is derived from case reports and series demonstrating compound heterozygosity in affected individuals. Notably, the variant c.920G>A (p.Gly307Glu) is reported in the index case along with additional segregating variants in other families. These cases—numbering approximately five probands (PMID:31434271)—underscore the autosomal recessive inheritance and emphasize the recurrent involvement of FOXRED1 in the disease process.

Functional studies further bolster the pathogenic role of FOXRED1 variants. Assays in patient fibroblasts reveal a marked reduction in complex I activity, and rescue experiments have validated the functional impact of these mutations (PMID:20818383, PMID:20858599). Collectively, these experiments demonstrate that the molecular mechanism underlying mitochondrial complex I deficiency involves impaired assembly and function of the respiratory chain complex.

No significant conflicting evidence has been reported, although the clinical presentation can be heterogeneous. The convergence of cohort studies, segregation data, and functional experiments all support a strong gene–disease association. Furthermore, the consistent experimental observations directly mirror the biochemical phenotypes observed in patients.

In summary, the integration of comprehensive genetic and functional evidence substantiates that FOXRED1 mutations are strongly associated with mitochondrial complex I deficiency. This synthesis not only supports diagnostic decision‑making and commercial assay development but also offers valuable insights for future research and publication.

Key Take‑home: FOXRED1 variant testing is essential for precise diagnosis and optimal management of patients with mitochondrial complex I deficiency.

References

• Journal of clinical medicine • 2019 • Identification and Characterization of New Variants in FOXRED1 Gene Expands the Clinical Spectrum Associated with Mitochondrial Complex I Deficiency PMID:31434271
• Molecular genetics and metabolism reports • 2019 • Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency PMID:30723688
• Human molecular genetics • 2010 • FOXRED1, encoding an FAD‑dependent oxidoreductase complex‑I‑specific molecular chaperone, is mutated in infantile‑onset mitochondrial encephalopathy PMID:20858599
• Nature genetics • 2010 • High‑throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency PMID:20818383

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