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AZFc deletions and spermatogenic failure: a population-based survey of 20,000 Y chromosomes.

ABSTRACT: Deletions involving the Y chromosome's AZFc region are the most common known genetic cause of severe spermatogenic failure (SSF). Six recurrent interstitial deletions affecting the region have been reported, but their population genetics are largely unexplored. We assessed the deletions' prevalence in 20,884 men in five populations and found four of the six deletions (presented here in descending order of prevalence): gr/gr, b2/b3, b1/b3, and b2/b4. One of every 27 men carried one of these four deletions. The 1.6 Mb gr/gr deletion, found in one of every 41 men, almost doubles the risk of SSF and accounts for ?2% of SSF, although <2% of men with the deletion are affected. The 1.8 Mb b2/b3 deletion, found in one of every 90 men, does not appear to be a risk factor for SSF. The 1.6 Mb b1/b3 deletion, found in one of every 994 men, appears to increase the risk of SSF by a factor of 2.5, although <2% of men with the deletion are affected, and it accounts for only 0.15% of SSF. The 3.5 Mb b2/b4 deletion, found in one of every 2,320 men, increases the risk of SSF 145 times and accounts for ?6% of SSF; the observed prevalence should approximate the rate at which the deletion arises anew in each generation. We conclude that a single rare variant of major effect (the b2/b4 deletion) and a single common variant of modest effect (the gr/gr deletion) are largely responsible for the AZFc region's contribution to SSF in the population.

SUBMITTER: Rozen SG

PROVIDER: S-EPMC3487143 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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AZFc deletions and spermatogenic failure: a population-based survey of 20,000 Y chromosomes.

Rozen Steven G SG Marszalek Janet D JD Irenze Kathryn K Skaletsky Helen H Brown Laura G LG Oates Robert D RD Silber Sherman J SJ Ardlie Kristin K Page David C DC

American journal of human genetics 20121025 5

Deletions involving the Y chromosome's AZFc region are the most common known genetic cause of severe spermatogenic failure (SSF). Six recurrent interstitial deletions affecting the region have been reported, but their population genetics are largely unexplored. We assessed the deletions' prevalence in 20,884 men in five populations and found four of the six deletions (presented here in descending order of prevalence): gr/gr, b2/b3, b1/b3, and b2/b4. One of every 27 men carried one of these four ...[more]

PMID: 23103232

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Project description:Azoospermic factor c (AZFc) deletions are the underlying cause in 10% of azoo- or severe oligozoospermia. Through extensive molecular analysis the precise genetic content of the AZFc region and the origin of its deletion have been determined. However, little is known about the effect of AZFc deletions on the functionality of germ cells at various developmental steps. The presence of normal, fertilization-competent sperm in the ejaculate and/or testis of the majority of men with AZFc deletions suggests that the process of differentiation from spermatogonial stem cells (SSCs) to mature spermatozoa can take place in the absence of the AZFc region. To determine the functionality of AZFc-deleted spermatogonia, we compared in vitro propagated spermatogonia from six men with complete AZFc deletions with spermatogonia from three normozoospermic controls. We found that spermatogonia of AZFc-deleted men behave similar to controls during culture. Short-term (18 days) and long-term (48 days) culture of AZFc-deleted spermatogonia showed the same characteristics as non-deleted spermatogonia. This similarity was revealed by the same number of passages, the same germ cell clusters formation and similar level of genes expression of spermatogonial markers including ubiquitin carboxyl-terminal esterase L1 (UCHL1), zinc finger and BTB domain containing 16 (ZBTB16) and glial cell line-derived neurotrophic factor family receptor alpha 1 (GFRA1), as well as germ cell differentiation markers including signal transducer and activator of transcription 3 (STAT3), spermatogenesis and oogenesis specific basic helix-loophelix 2 (SOHLH2), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and synaptonemal complex protein 3 (SYCP3). The only exception was melanoma antigen family A4 (MAGEA4) which showed significantly lower expression in AZFc-deleted samples than controls in short-term culture while in long-term culture it was hardly detected in both AZFc-deleted and control spermatogonia. These data suggest that, at least in vitro, spermatogonia of AZFc-deleted men are functionally similar to spermatogonia from non-deleted men. Potentially, this enables treatment of men with AZFc deletions by propagating their SSCs in vitro and autotransplanting these SSCs back to the testes to increase sperm counts and restore fertility.

Dataset Information

AZFc deletions and spermatogenic failure: a population-based survey of 20,000 Y chromosomes.

Publications

AZFc deletions and spermatogenic failure: a population-based survey of 20,000 Y chromosomes.

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