RHOXF1 – Male Infertility

Deleterious variants in the X‑linked gene RHOXF1 have been implicated in male infertility, particularly in individuals presenting with oligozoospermia and azoospermia. In a well‐characterized study involving a cohort of 1201 infertile Chinese men, four unrelated probands were identified with hemizygous variants in RHOXF1 (PMID:38258527). These cases exhibited a spectrum of variant types, including both missense and loss‑of‐function changes, and one patient’s testicular biopsy revealed a Sertoli cell‑only syndrome consistent with the absence of RHOXF1 protein expression. Such clinical observations accentuate the role of RHOXF1 in spermatogenesis and underscore its relevance in the diagnostic evaluation of male infertility. The convergence of genetic and clinical findings in these studies provides a solid foundation for interpreting the pathogenic implications of RHOXF1 variants. This body of evidence is critical for clinicians when considering genetic testing and personalized treatment options in infertile males.

The genetic evidence supporting this association is robust, driven by the identification of deleterious variants in four independent probands. Among these, the nonsense variant c.478C>T (p.Arg160Ter) stands out as a clear loss‑of‑function allele. Additionally, other missense variants—c.388G>A (p.Val130Met), c.272C>T (p.A91V), and c.467C>T (p.A156V)—support the pathogenic spectrum attributable to RHOXF1 mutations. Such findings, observed in multiple unrelated cases, reinforce the X‑linked pattern of inheritance and the gene’s critical influence on the male reproductive phenotype (PMID:38258527). The recurrence of these variants across independent cohorts further validates their clinical significance. Overall, the genetic data offer compelling evidence for the involvement of RHOXF1 in male infertility.

Functional experiments provide an additional, mechanistic layer of evidence. In vitro analyses showed that RHOXF1 mutations result in significantly reduced protein levels in HEK293T cells, with specific variants (p.Val130Met, p.A156V, and p.Arg160Ter) causing aberrant protein accumulation in cytoplasmic particles. Moreover, luciferase assays demonstrated that these mutations disrupt the regulatory activity on the DMRT1 promoter, a key factor in the spermatogenesis cascade (PMID:38258527). These experimental findings are consistent with the clinical phenotypes observed and offer a mechanistic explanation for how impaired RHOXF1 function contributes to defective spermatogenesis. Such concordance between the functional data and the observed patient phenotype strengthens the biological plausibility of the gene‐disease association.

No significant conflicting evidence was noted in the current body of literature. All available case reports and functional assessments consistently support the pathogenic role of RHOXF1 in male infertility. Although extended familial segregation data were not provided, the independent identification of deleterious variants and corroborative functional studies across multiple probands greatly diminish any uncertainty regarding this association. This uniformity across different lines of evidence offers clinicians and researchers confidence in interpreting RHOXF1 variants when evaluating patients with male infertility. The absence of contradictory data further solidifies the gene’s clinical validity.

In conclusion, the integration of genetic findings and functional evidence clearly establishes a strong association between RHOXF1 and male infertility. The identification of recurrent deleterious variants, such as c.478C>T (p.Arg160Ter), in multiple unrelated probands, combined with functional assays demonstrating impaired protein function and disrupted downstream regulatory activity, underscores the gene’s critical role in spermatogenesis (PMID:38258527). This comprehensive evaluation not only enhances our understanding of the molecular etiology of male infertility but also supports the clinical utility of incorporating RHOXF1 testing into diagnostic workflows. Clinicians can therefore confidently use these findings to guide diagnostic decision‑making and inform targeted therapeutic strategies.

References

• Molecular Human Reproduction • 2024 • Deleterious variants in X‑linked RHOXF1 cause male infertility with oligo‑ and azoospermia PMID:38258527

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