SFXN4 – Mitochondrial Disease

Recent studies have identified loss‐of‐function mutations in SFXN4 as causative for mitochondrial disease (PMID:24119684). In the reported cases, two unrelated probands were found to harbor distinct SFXN4 variants, including the frameshift mutation c.668del (p.Lys223fs), which supports a loss‐of‐function mechanism. The clinical presentation in these patients was consistent with mitochondrial dysfunction, and one case additionally exhibited macrocytic anemia suggestive of an overlapping clinical phenotype. Segregation analysis was limited, with no additional affected relatives documented (PMID:24119684).

Genetic evidence is bolstered by the detection of multiple loss‐of‐function alleles in the probands, including splice and frameshift variants, which together indicate that disruption of SFXN4 function predisposes to the mitochondrial disease phenotype. The recurrence of these deleterious variants in independent patients reinforces the clinical relevance of SFXN4 in disease pathogenesis (PMID:24119684).

Functional studies further substantiate this association. In vitro experiments and zebrafish knockdown assays demonstrated that SFXN4 deficiency leads to profound impairment of Fe‑S cluster biogenesis, mitochondrial respiration, and iron homeostasis. These well‐designed assays, including rescue experiments in patient fibroblasts, provide key experimental support that the pathogenic mechanism operates via loss of SFXN4 function (PMID:31873120).

While the number of probands is limited, the convergence of consistent genetic findings and robust functional evidence underpins a moderately strong gene–disease association. Such an integrated data set underlines the potential diagnostic utility of SFXN4 variant screening in patients with mitochondrial dysfunction and guides targeted therapeutic strategies.

The overall data support the clinical utility of SFXN4 evaluation in cases of suspected mitochondrial disease, with multi‐modal evidence enhancing diagnostic decision‑making and justifying further research and commercial development.

Key Take‑home: SFXN4 loss‑of‑function mutations represent a clinically actionable contributor to mitochondrial disease, with converging genetic and experimental evidence reinforcing its role in pathogenesis.

References

• American journal of human genetics • 2013 • Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4 PMID:24119684
• Scientific reports • 2019 • Sideroflexin 4 affects Fe‑S cluster biogenesis, iron metabolism, mitochondrial respiration and heme biosynthetic enzymes PMID:31873120

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