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This summary details the association between RHOXF1 and azoospermia. In a study of a cohort of 1201 infertile Chinese men, four unrelated male probands were identified with hemizygous variants in the X‑linked RHOXF1 gene (PMID:38258527). The affected individuals exhibited classical features of azoospermia, characterized by the absence of sperm due to defective spermatogenesis.
The genetic evidence is built on the identification of four distinct variants, including three missense and one nonsense variant. In particular, the variant c.478C>T (p.Arg160Ter) was observed, and similar findings were corroborated across both case report and multi‐patient study data (PMID:38258527). Although no extended familial segregation data were provided, the consistent identification of hemizygous variants in probands lends weight to a causal relationship.
Functional assessments further strengthen this association. In vitro experiments demonstrated that RHOXF1 mutations lead to a significant reduction of protein levels in HEK293T cells and aberrant accumulation within cytoplasmic particles. Moreover, luciferase assays revealed that the p.Arg160Ter mutation disrupts the regulation of crucial downstream targets, such as the DMRT1 promoter, suggesting a direct impact on spermatogenesis (PMID:38258527).
There is no conflicting evidence reported in the current literature regarding the role of RHOXF1 in azoospermia, and the experimental data are concordant with the observed clinical phenotypes. This integrated evidence from both genetic and functional domains supports the pathogenic role of RHOXF1 in azoospermia.
In summary, the consistent identification of deleterious hemizygous variants—including c.478C>T (p.Arg160Ter)—combined with robust functional assays, establishes a strong causal link between RHOXF1 and azoospermia. This evidence is significant for diagnostic decision‑making and has potential commercial as well as translational implications in the management of male infertility.
Key Take‑home sentence: RHOXF1 mutations represent a strong, causative genetic factor in azoospermia, with both genetic and functional studies underpinning its clinical utility.
Gene–Disease AssociationStrongFour unrelated probands (PMID:38258527) with concordant findings from both genetic and functional experiments support this association. Genetic EvidenceStrongIdentification of four hemizygous variants—including c.478C>T (p.Arg160Ter)—in probands, with mutation types spanning missense and nonsense changes, establishes robust genetic evidence (PMID:38258527). Functional EvidenceStrongIn vitro assays demonstrating reduced protein levels, aberrant cytoplasmic accumulation, and impaired promoter regulation of DMRT1 confirm the functional impact of RHOXF1 mutations (PMID:38258527). |