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Multiple genetic association studies have investigated the role of TNP2 in male infertility (MONDO_0005372). In one study, a cohort of 125 infertile men (PMID:19602509) was compared to 160 controls, and although variants were identified in the protamine locus, direct evidence for TNP2 was not statistically robust. A subsequent study involving 96 infertile men (PMID:25246894) screened for single nucleotide polymorphisms including one in TNP2, where the frequency of the variant allele (reported as TNP2 G1272C) was marginally higher in cases; however, statistical significance was not achieved. These findings suggested that, while TNP2 is a candidate gene at the protamine locus, its individual contribution to azoospermia and oligozoospermia remains uncertain.
A third, more recent study examined 120 idiopathic infertile cases (PMID:35103426) and identified a significant association with the TNP2 rs199536093 GG genotype. Although this study provided moderate statistical evidence, the overall genetic data are derived from modest sample sizes and case‐control analyses without robust familial segregation data. Hence, the current genetic evidence for TNP2 remains not fully conclusive.
The genetic evidence has been further contextualized by the identification of the variant c.1272G>C (p.Gly424Arg) in TNP2 from the variant list. This variant was selected because it meets the HGVS criteria and serves as an example of a rare missense change reported in these studies. Despite its potential pathogenic impact, the recurrent nature and functional consequences remain to be fully characterized.
The pathogenic mechanism for TNP2 in male infertility is currently thought to be related to abnormal chromatin compaction during spermatogenesis. However, functional studies are sparse and have not yet provided definitive data regarding the impact of TNP2 variants on protein function or spermatogenic failure. Further experimental work, including cellular and animal models, is necessary to clarify its role.
In summary, the association between TNP2 (HGNC:11952) and male infertility is supported by several case‑control studies that report limited and somewhat conflicting genetic evidence. There is a paucity of segregation data and functional evidence, which limits the strength of the overall association despite a statistically significant finding in one recent study. Additional independent and mechanistic studies are needed to advance our understanding of the gene’s pathogenic role and improve its diagnostic utility.
Key Take‑home: While current evidence suggests a possible involvement of TNP2 in male infertility, further comprehensive studies are essential before its use in clinical diagnostics can be fully endorsed.
Gene–Disease AssociationLimitedThree independent studies (125 infertile men [PMID:19602509], 96 infertile men [PMID:25246894], and 120 infertile men [PMID:35103426]) provide modest and inconsistent evidence, with limited segregation and replication data. Genetic EvidenceLimitedVariants in TNP2 have been identified in small case-control studies with one study reporting a statistically significant association, yet the overall variant spectrum remains limited and lacks robust segregation data. Functional EvidenceLimitedCurrent functional studies are sparse and do not provide adequate demonstration of the mechanism by which TNP2 variants could lead to male infertility. |