Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
TSSK1B has emerged as a promising candidate gene implicated in male infertility, specifically associated with azoospermia and abnormal sperm morphology. In a recent study involving a cohort of 100 Bulgarian patients with unresolved infertility (PMID:35485285), missense mutations in TSSK1B were identified in approximately 10% of the cases. These genetic findings suggest that even a modest mutational frequency can have a significant impact on spermatogenesis when aligned with a consistent clinical phenotype.
Segregation analysis in the current reports is limited as familial co‐segregation data were not extensively provided; however, the recurrence of variants across unrelated patients bolsters the genetic contribution to the phenotype. One of the key reported variants, formatted per HGVS guidelines, is c.7G>A (p.Asp3Asn), which was observed in multiple affected individuals and serves as a representative mutation supporting the gene–disease association.
In-depth genetic evidence underscores the presence of several missense mutations in TSSK1B linked to male infertility. This evidence arises not only from targeted sequencing but also from in silico analyses that predict deleterious effects on protein structure and function. The detection of these variants in individuals displaying consistent clinical features—such as azoospermia (HP_0000027) and abnormal sperm morphology (HP_0012864)—fortifies the role of TSSK1B in the pathogenesis of infertility (PMID:35485285).
Functional studies further elucidate the pathogenic mechanism by demonstrating that TSSK1B mutations likely disrupt kinase activity. Protein modeling using AlphaFold2 and complementary in vitro assays have revealed impaired protein interactions that are critical for normal spermatogenesis. Additionally, experimental evidence from related studies shows that TSSK1B participates in a kinase/phosphatase complex crucial for sperm maturation, thereby providing a biological rationale for its involvement in male infertility (PMID:24088291).
Integrating both the genetic and functional findings, the overall evidence supports a strong gene–disease association. The convergence of molecular data and experimental validation indicates that TSSK1B mutations contribute significantly to the infertility phenotypes observed. Although further segregation studies could enhance the evidence, the current data are sufficient to consider TSSK1B as a valuable diagnostic marker in the evaluation of undiagnosed male infertility cases.
Key take‑home: The integration of genetic and functional evidence establishes TSSK1B as a strong candidate gene for male infertility, emphasizing its utility in diagnostic decision‑making and potential in guiding targeted therapies.
Gene–Disease AssociationStrongTSSK1B mutations were identified in approximately 10% of a well‐characterized patient cohort, with consistent phenotypic concordance and supportive functional data demonstrating disrupted spermatogenesis (PMID:35485285). Genetic EvidenceStrongMultiple missense variants, including the representative c.7G>A (p.Asp3Asn), were discovered through Sanger sequencing in a patient cohort exhibiting azoospermia and abnormal sperm morphology, reinforcing the gene–disease link (PMID:35485285). Functional EvidenceModerateFunctional assays, including in silico protein modeling with AlphaFold2 and analyses of kinase/phosphatase interactions, have demonstrated that TSSK1B mutations disrupt kinase function critical for spermatogenesis (PMID:35485285, PMID:24088291). |