TDRD6 – Oligospermia

TDRD6 encodes a testis-specific chromatoid body protein critical for spermiogenesis. Bi-allelic variants in TDRD6 have been implicated in autosomal recessive oligospermia, particularly the oligoasthenoteratozoospermia (OAT) phenotype characterized by low sperm count, impaired motility and abnormal head morphology. Evidence arises from consanguineous pedigrees and multi-patient cohorts, with concordant functional data in cellular assays and animal models supporting a direct causal role.

Initial genetic evidence came from a 38-year-old male with OAT from a consanguineous family who harbored a homozygous missense variant c.1259A>G (p.Tyr420Cys) ([PMID:29551503]). This variant co-segregated with the phenotype in the family and was absent from population databases. Subsequent whole-exome sequencing in five unrelated Chinese individuals confirmed bi-allelic TDRD6 variants, including homozygous loss-of-function alleles in two families, all presenting with severe OAT and acrosomal hypoplasia ([PMID:38341271]). More recently, an additional patient with severe OAT was found to carry a homozygous stop-gain variant c.1825G>T (p.Gly609Ter) ([PMID:39331689]).

The variant spectrum includes at least one pathogenic missense change (p.Tyr420Cys) and multiple loss-of-function alleles (e.g., c.1825G>T (p.Gly609Ter)), consistent with a loss-of-function mechanism. No recurrent or founder variants have yet been reported, and allele frequencies are extremely low or absent in large control cohorts.

Functional studies in Tdrd6-knockout mice recapitulate the human OAT phenotype, demonstrating disrupted chromatoid body architecture, acrosomal defects and blocked spermiogenesis, as well as failed assembly of key CB components (DDX4, UPF1) in round spermatids ([PMID:38341271]; [PMID:39331689]). Ultrastructural analyses, immunofluorescence and scRNA-seq of patient germ cells revealed defective mRNA metabolism pathways critical for spermatid differentiation, further corroborating the pathogenic impact of TDRD6 deficiency ([PMID:38341271]).

These data collectively support a loss-of-function mechanism whereby TDRD6 deficiency disrupts chromatoid body dynamics, nonsense-mediated decay and acrosome biogenesis, leading to autosomal recessive oligospermia and unfavorable assisted reproduction outcomes. No conflicting reports of benign variation or alternative phenotypes have been described to date.

Overall, the integration of genetic segregation in consanguineous families, multiple unrelated probands with bi-allelic variants, and robust functional modeling in mice and patient cells provides strong evidence for TDRD6 as a diagnostic target in male infertility. Key Take-home: Bi-allelic loss-of-function and missense variants in TDRD6 cause autosomal recessive oligospermia with consistent genetic and functional corroboration.

References

• Gene • 2018 • TDRD6 is associated with oligoasthenoteratozoospermia by sequencing the patient from a consanguineous family. PMID:29551503
• Journal of Medical Genetics • 2024 • Bi-allelic variants in chromatoid body protein TDRD6 cause spermiogenesis defects and severe oligoasthenoteratozoospermia in humans. PMID:38341271
• Journal of Cellular and Molecular Medicine • 2024 • Loss-of-function variant in TDRD6 cause male infertility with severe oligo-astheno-teratozoospermia in human and mice. PMID:39331689

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