SPAG6 – Male Infertility

This summary evaluates the evidence for an association between SPAG6 (HGNC:11215) and male infertility (MONDO_0005372). The study by the Journal of assisted reproduction and genetics (2020) reported a patient with severe asthenoteratospermia who harbored compound heterozygous SPAG6 mutations, indicating a disruption in flagellar biogenesis and function (PMID:32124190).

In assessing clinical validity, the current evidence is limited by the identification of a single proband with confirmed compound heterozygous mutations. The reported genetic findings, including the frameshift variant c.587del (p.Lys196SerfsTer6), were demonstrated in a sporadic case with appropriate ICSI management outcomes. This case, although isolated, is supported by rigorous molecular diagnostics and adheres to autosomal recessive inheritance patterns (PMID:32124190).

Genetic evidence indicates an autosomal recessive pattern for SPAG6-linked male infertility. The available data document one proband carrying the reported frameshift variant c.587del (p.Lys196SerfsTer6), with no additional affected relatives reported for segregation analysis. The variant is consistent with a loss-of-function mechanism, as predicted by its nature and supportive functional data (PMID:32124190).

Functional assessments further bolster the mechanistic plausibility of this gene–disease relationship. In vitro studies have demonstrated that SPAG6 is essential for microtubule stability, ciliogenesis, and cellular motility. Experimental work in Spag6-deficient mouse embryonic fibroblasts revealed significant defects in cell morphology and cilia formation (PMID:26585507), while complementary studies in neuronal models underscored its role in cytoskeletal organization (PMID:28819108).

Integrating genetic and experimental data, the disruption of SPAG6 function appears to impair the structural integrity of sperm flagella, thereby contributing to the severe asthenoteratospermia observed in affected individuals. The convergence of a confirmed loss-of-function mutation with supportive in vitro functional studies reinforces the pathogenic mechanism underlying SPAG6-associated male infertility.

Key take‑home: Although current clinical evidence is limited to a single proband, the complementary functional data and the clear loss‑of‑function mechanism provide a valuable diagnostic clue for male infertility, supporting informed decision‑making in reproductive assistance and guiding further research toward clinical validation.

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
• Scientific reports • 2015 • Sperm Associated Antigen 6 (SPAG6) Regulates Fibroblast Cell Growth, Morphology, Migration and Ciliogenesis PMID:26585507
• Scientific reports • 2017 • Spag6 Mutant Mice Have Defects in Development and Function of Spiral Ganglion Neurons, Apoptosis, and Higher Sensitivity to Paclitaxel PMID:28819108

Evidence Based Scoring (AI generated)