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FOXRED1 – Mitochondrial Disease

FOXRED1 encodes a mitochondrial FAD-dependent oxidoreductase assembly factor essential for complex I biogenesis. Biallelic pathogenic variants in FOXRED1 cause autosomal recessive mitochondrial disease (MONDO:0044970), characterized predominantly by mitochondrial myopathy (HP:0003737).

Genetic studies have identified at least 10 unrelated probands with FOXRED1-associated mitochondrial disease, including consanguineous homozygous cases and compound heterozygotes (PMID:33613441; PMID:38283147). Variant spectrum includes nonsense, frameshift, canonical splice-site, and missense changes; for example, c.1054C>T (p.Arg352Trp) disrupts the FAD-binding domain (PMID:20858599).

Segregation analysis in a consanguineous Iranian-Jewish pedigree demonstrated homozygosity for c.1054C>T segregating with infantile-onset encephalopathy among affected relatives, consistent with autosomal recessive inheritance (PMID:20858599).

Functional assays show loss-of-function mechanism: cDNA complementation of patient fibroblasts restored complex I steady-state levels and enzymatic activity, confirming causality of FOXRED1 variants (PMID:20818383; PMID:20858599). Mutant cells exhibit marked reduction of assembled complex I holoenzyme and NADH dehydrogenase activity.

No studies have reported conflicting evidence for FOXRED1 in mitochondrial disease. Cumulative genetic and experimental data satisfy ClinGen strong criteria for gene–disease validity.

Key take-home: FOXRED1 should be included in diagnostic panels for autosomal recessive mitochondrial disorders and considered in differential diagnosis of complex I deficiency.

References

  • 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
  • Frontiers in neurology • 2021 • Clinical and Genetic Characteristics of Mitochondrial Encephalopathy Due to FOXRED1 Mutations: Two Chinese Case Reports and a Review of the Literature PMID:33613441
  • Frontiers in genetics • 2023 • Expanding the genetic spectrum of mitochondrial diseases in Tunisia: novel variants revealed by whole-exome sequencing PMID:38283147

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

At least 10 probands ([PMID:33613441]; [PMID:38283147]), autosomal recessive segregation in multiple families ([PMID:20858599]), and concordant functional complementation ([PMID:20818383]).

Genetic Evidence

Strong

Ten probands with biallelic FOXRED1 variants in unrelated families, including homozygous and compound heterozygous changes, with segregation in a consanguineous pedigree.

Functional Evidence

Strong

cDNA complementation and rescue of complex I activity in patient fibroblasts ([PMID:20818383]; [PMID:20858599]) and concordant mitochondrial biochemical assays demonstrating reduced complex I assembly and activity.