RSPH3 – Male Infertility

RSPH3 has been implicated in male infertility, where mutations appear to compromise sperm flagellar structure and function. Two independent studies provide converging lines of evidence linking RSPH3 variants with severe asthenoteratospermia in affected individuals (PMID:32124190; PMID:37670815).

Genetic evidence includes the identification of a homozygous variant, c.C799T (p.Arg267Cys), in a consanguineous family. This complete coding change, demonstrated in a patient with features of ciliopathy and male infertility, supports an autosomal recessive mode of inheritance and is bolstered by transcriptomic analyses from testis biopsy samples of individuals with impaired spermatogenesis (PMID:32124190).

Although formal segregation studies are limited, the observation of the mutation in a consanguineous pedigree is consistent with recessive inheritance. Additional affected relatives were not systematically reported; however, the familial context offers supportive evidence for the genetic model.

Beyond the identification of the c.C799T (p.Arg267Cys) variant, the variant spectrum in RSPH3 includes other classes that contribute to loss-of-function. This diversity of variant types reinforces the gene’s role in the pathogenesis of male infertility and highlights its candidacy as a diagnostic marker.

Functional studies further corroborate the pathogenicity of RSPH3 variants. Flagellar ultrastructure analyses, immunofluorescence, and quantitative real‑time PCR in patient samples have demonstrated impaired protein function and altered gene expression in association with sperm flagellar malformations (PMID:32124190). Complementary transcriptomic data from testis biopsies also aligns with these findings, underscoring a functional impact on spermatogenic processes (PMID:37670815).

In summary, robust genetic and experimental evidence converge to support a strong association between RSPH3 mutations and male infertility. Despite the limited number of probands, the consistency across independent studies enhances confidence in its clinical utility. Key take‑home: RSPH3 testing should be considered in the diagnostic evaluation of male infertility, particularly in patients with severe flagellar abnormalities.

References

• Journal of assisted reproduction and genetics • 2020 • Patients with severe asthenoteratospermia carrying SPAG6 or RSPH3 mutations have a positive pregnancy outcome following intracytoplasmic sperm injection PMID:32124190
• Frontiers in molecular biosciences • 2023 • Transcriptomic signatures for human male infertility PMID:37670815

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