Spermatogenic failure and the Y chromosome

Abstract

The Y chromosome harbors a number of genes essential for testis development and function. Its highly repetitive structure predisposes this chromosome to deletion/duplication events and is responsible for Y-linked copy-number variations (CNVs) with clinical relevance. The AZF deletions remove genes with predicted spermatogenic function en block and are the most frequent known molecular causes of impaired spermatogenesis (5-10% of azoospermic and 2-5% of severe oligozoospermic men). Testing for this deletion has both diagnostic and prognostic value for testicular sperm retrieval in azoospermic men. The most dynamic region on the Yq is the AZFc region, presenting numerous NAHR hotspots leading to partial losses or gains of the AZFc genes. The gr/gr deletion (a partial AZFc deletion) negatively affects spermatogenic efficiency and it is a validated, population-dependent risk factor for oligozoospermia. In certain populations, the Y background may play a role in the phenotypic expression of partial AZFc rearrangements and similarly it may affect the predisposition to specific deletions/duplication events. Also, the Yp contains a gene array, TSPY1, with potential effect on germ cell proliferation. Despite intensive investigations during the last 20 years on the role of this sex chromosome in spermatogenesis, a number of clinical and basic questions remain to be answered. This review is aimed at providing an overview of the role of Y chromosome-linked genes, CNVs, and Y background in spermatogenesis.

A rare karyotype of nonmosaic isodicentric (Y) (p11.31) with azoospermia and short stature

“…Halder et al detected copy number variations (CNVs) in 68 cases of testicular maturation arrest and the AZFc gain was observed in 8.8% of the cases (Halder, Kumar, Jain, & Iyer, ). TSPY1 and TSPY2 are testis‐specific expressed genes, which involves in spermatocyte proliferation and differentiation (Krausz & Casamonti, ). TSPY2 gene gains is also suspected as an aetiological factor with male infertility (Vodicka et al, ), which was observed in 23% of MA cases (Halder et al, ).…”

Human Y Chromosome and Male Infertility: Forward and Back from Azoospermia Factor Chromatin Structure to Azoospermia Factor Gene Function

“…Complete AZFc microdeletions were found with high frequency (5-15%), however, only in genomic DNA samples of infertile men with a severe reduction in sperm number (<10 million per mL ejaculate) and including the OAT syndrome [22,[86][87][88] . These studies clearly show that complete AZFc deletions interfere with the spermatogenic maturation process, reducing its efficiency and causing hypospermatogenesis as the primary mutation effect.…”

“…These studies clearly show that complete AZFc deletions interfere with the spermatogenic maturation process, reducing its efficiency and causing hypospermatogenesis as the primary mutation effect. Age-dependent secondary mutation effects might -but must not -eventually cause a complete absence of mature spermatozoa (i.e., azoospermia) in the man's semen fluid [13,88] .…”

Clinical and molecular characterization of Y microdeletions and X‐linked CNV67 implications in male fertility: a 20‐year experience

“…AZFb deletions are mainly associated with germ cell maturation arrest (Costa et al ., ; Soares et al ., ). The most common deletion, in the AZFc region, encompassing DAZ (Deleted in AZoospermia) gene, displays a larger spectrum of clinical and histological manifestations, with variable sperm production capacity; therefore, most of these men show residual spermatogenesis which allows spermatozoa retrieval for in vitro fertilization by intracytoplasmic sperm injection (ICSI) (Vogt et al ., ; Hopps, ; Vogt & Fernandes, ; Pastuszak & Lamb, ; Krausz et al ., ; Goncalves et al ., ; Krausz & Casamonti, ). Furthermore, the AZFc region may be partially deleted (b1/b3, b2/b3 and gr/gr deletions) leading to copy number variations of some genes that play a role in spermatogenesis which results in different amounts of proteins produced and a wide heterogeneity in sperm counts and fertile status depending on the Y genetic background (Fernandes et al ., ; Navarro‐Costa et al ., ; Krausz et al ., ; Colaco & Modi, ).…”