Clinical Research Directory

Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men

Sponsor: South Valley University

Summary

Infertility remains a significant global burden. Estimates suggest that 10-15% of couples worldwide experience infertility, with male infertility being the underlying cause in 20-50% of cases. For the majority of cases however the etiology remains unknown, and is termed idiopathic infertility. Azoospermia, absence of spermatozoa in the semen, is one of the most common reasons for infertility in men, with a prevalence of 1% in the general population, and over 15% in infertile men. Oligozoospermia is a major cause of male infertility, yet its genetic basis remains partially understood. Oligozoospermia refers to sperm concentrations below established reference limits (e.g. 16 million/ml, 95% confidence interval 15-18 million/ml; WHO 2021). Numerous studies have demonstrated a strong genetic basis for oligozoospermia, with genetic abnormalities, such as abnormalities in chromosome number or structure, azoospermia factor region (AZF) deletion on the Y chromosome and cystic fbrosis transmembrane conduction regulator (CFTR) gene mutations, reported in men with otherwise unexplained oligozoospermia and azoospermia. Moreover, previous studies have identifed more than 400 genes that are specifcally or potentially associated with fertility regulation while potentially contributing to the widespread genetic heterogeneity associated with dyszoospermia. For example, mutations in RPL10L and MAGEB have been reported to cause oligozoospermia. However, mutations in only a few genes have been shown to cause male infertility, and the candidate pathogenic genes for oligozoospermia still need to be studied further. Recent studies have implicated the Tudor Domain Containing 9 (TDRD9) gene in the regulation of spermatogenesis through its role in piRNA pathway and transposon silencing. A 2024 study identified compound heterozygous mutations-c.1115+3A\>G (splicing variant) and c.958delC (frameshift variant)-in a Chinese family with idiopathic oligozoospermia, resulting in aberrant splicing and truncated TDRD9 protein products. Tudor domain-containing protein 9 (TDRD9) is an RNA helicase that is highly expressed in germlines. TDRD9 expression has been detected in mitotic spermatogonia, meiotic spermatocytes and haploid spermatids in the testis. In male infertility cases, TDRD9 has been reported to be involved in the silencing of long intersperm-1 retrotransposons, suggesting an association between TDRD9 mutations and non-obstructive azoospermia. TDRD9 is implicated in spermatogenesis and piRNA pathway integrity. Variants may affect sperm quality and response to treatments. L-carnitine is widely used as an antioxidant and metabolic supplement shown to improve sperm parameters in some infertile men. This study will test whether TDRD9 mutation status predicts therapeutic benefit from L-carnitine.

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