Genetic Landscape of Nonobstructive Azoospermia and New Perspectives for the Clinic

Abstract

Nonobstructive azoospermia (NOA) represents the most severe expression of male infertility, involving around 1% of the male population and 10% of infertile men. This condition is characterised by the inability of the testis to produce sperm cells, and it is considered to have an important genetic component. During the last two decades, different genetic anomalies, including microdeletions of the Y chromosome, karyotype defects, and missense mutations in genes involved in the reproductive function, have been described as the primary cause of NOA in many infertile men. However, these alterations only explain around 25% of azoospermic cases, with the remaining patients showing an idiopathic origin. Recent studies clearly suggest that the so-called idiopathic NOA has a complex aetiology with a polygenic inheritance, which may alter the spermatogenic process. Although we are far from a complete understanding of the molecular mechanisms underlying NOA, the use of the new technologies for genetic analysis has enabled a considerable increase in knowledge during the last years. In this review, we will provide a comprehensive and updated overview of the genetic basis of NOA, with a special focus on the possible application of the recent insights in clinical practice.

Cracd Marks the First Wave of Meiosis during Spermatogenesis and Is Mis-Expressed in Azoospermia Mice

“…We previously demonstrated that Cracd mRNA is expressed in adult mouse testis within the germ cells [ 8 ]. To further define the transcriptional temporal profile and uncover when and where within mouse spermatogenesis Cracd mRNA is initially expressed, we used in situ hybridization to map Cracd in staged postnatal, juvenile (P5-4 weeks), and adult (4-month-old) C57BL/6J mice [ 1 , 21 ].…”

“…Azoospermia, a condition in which there are no spermatozoa in the ejaculate, occurs in approximately 1% of all men and ranges between 10% and 15% among infertile men [ 7 ]. Moreover, azoospermia may occur because of an obstruction in the reproductive tract (called obstructive azoospermia) or the more prevalent condition of inadequate spermatozoa nor late-stage spermatids production (called non-obstructive azoospermia) which results in male infertility [ 8 ]. Given that non-obstructive azoospermia is most likely related to a failure in the spermatogenic process, we need to focus on identifying and further understanding the genes involved in testicular spermatogenesis and aberrant signaling pathways that cause male infertility.…”

“…Given that non-obstructive azoospermia is most likely related to a failure in the spermatogenic process, we need to focus on identifying and further understanding the genes involved in testicular spermatogenesis and aberrant signaling pathways that cause male infertility. As the mammalian testis ranks among the top tissues with respect to transcriptome complexity, expressing the most (~84%) genes [ 5 ] and there are thought to be multiple mechanisms that may underlie non-obstructive azoospermia, detailed information regarding the cell-type-specific expression patterns of spermatogenic genes is needed to prioritize potential pathogenic variants that contribute to the pathogenesis of azoospermia [ 8 ]. Moreover, establishing when and where uncharacterized spermatogenic genes are expressed is of crucial importance to understanding or predicting their physiological role and how they may interact to form the complex expression networks that underlie spermatogenesis and testis development.…”

Preliminary investigation of the function of hsa_circ_0049356 in nonobstructive azoospermia patients

“…Spermatogenesis is a polygenic and multistep process that involves a variety of regulatory molecules (Wang et al., 2018; Yuan et al., 2019). NOA represents the most severe male infertility condition, and various genetic anomalies have been reported to be involved in the progression of disease (Cervan‐Martin et al., 2020; Vogt et al., 2019). With a complex genetic background, the pathogenesis of INOA remains unclear.…”

“…Azoospermia can be divided into two main categories: mechanical obstruction of vas deferens (obstructive azoospermia, OA) and primary spermatogenic failure (nonobstructive azoospermia, NOA). Approximately 60% of azoospermia patients are diagnosed with NOA (Cissen et al., 2016) and the common causes are primary testicular factors, including genetic mutations, karyotype aberrations, Y chromosome microdeletions, hypergonadotropic hypogonadism and varicocele (Cervan‐Martin, Castilla, Palomino‐Morales, & Carmona, 2020; Yatsenko et al., 2015). However, only about 25% of the NOA cases can be attributed to the above reasons, and the aetiology of the remaining patients is still unclear and in those patients, it is defined as idiopathic nonobstructive azoospermia (INOA; Alfano et al., 2019; Cissen et al., 2016).…”