Genomic and genetic variation in E2F transcription factor-1 in men with nonobstructive azoospermia

Abstract

Objective To identify gene dosage changes associated with non-obstructive azoospermia (NOA) using array comparative genomic hybridization (aCGH). Design Prospective study. Patients 110 men with NOA and 78 fertile controls. Settings Medical School Interventions None Main Outcome Measure The study has four distinct analytic components: aCGH, a molecular karyotype that detects copy-number-variations (CNV), Taqman-CNV assays to validate CNVs, mutation identification by Sanger sequencing and histologic analyses of testicular tissues. Results A microduplication at 20q11.22 encompassing E2F1 was identified in one of eight men with NOA analyzed using aCGH. CNVs were confirmed and an additional 102 men with NOA screened using Taqman CNV assays for a total of 110 NOA men analyzed for CNVs in E2F1. Eight of 110 (7.3%) NOA men had microduplications or microdeletions of E2F1 that were absent in fertile controls. Conclusions E2F1 microduplications or microdeletions are present in NOA men (7.3%). Duplications or deletions of E2F1 occur very rarely in the general population (0.011%), but E2F1 gene dosage changes, previously reported only in cancers, are present in a subset of NOA men. These results recapitulate the infertility phenotype seen in mice lacking or over-expressing E2f1.

E2F1 copy number variations contribute to spermatogenic impairment and cryptorchidism by increasing susceptibility to heat stress

“…This study showed an association between altered E2F1 copies and spermatogenic failure, expanding previous preliminary results obtained only in NOA (Jorgez et al, 2015). In particular, we found E2F1 CNVs in 2.5% of men with NOA and oligozoospermia of unknown origin and in 6.0% of cases associated with cryptorchidism.…”

“…E2F1 is, in fact, a transcription factor belonging to E2F family and whose main function is to trigger the entry into S phase of cell cycle or apoptotic process. Supporting this biological function, Jorgez et al (2015) found altered E2F1 copy number in 8 out of 110 patients with NOA. In particular, it has been demonstrated that mouse E2f1 protein plays an important role in the first wave of spermatogenesis and in adult mouse testes (Rotgers et al, 2015).…”

“…In particular, we found associations between E2F1 CNV and TGCT risk, Rocca et al (2017) and Jorgez et al (2015) reported an association with non-obstructive azoospermia (NOA). In particular, we found associations between E2F1 CNV and TGCT risk, Rocca et al (2017) and Jorgez et al (2015) reported an association with non-obstructive azoospermia (NOA).…”

“…Recent studies have reported that CNVs involving the E2F1 gene are linked to diseases of the reproductive tract. In particular, we found associations between E2F1 CNV and TGCT risk, Rocca et al (2017) and Jorgez et al (2015) reported an association with non-obstructive azoospermia (NOA). E2F1 (UniprotKB: Q01094) is a transcription factor with high binding affinity for the retinoblastoma tumor suppressor (RB) protein (Sengupta & Henry, 2015) and represents the most frequent member of the E2F family.…”

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

“…E2F1 is post‐transcriptionally silenced in the pachytene spermatocytes and GCNIS‐cells in the human testis (Novotny et al ., 2007). Furthermore, E2f1 microduplications and microdeletions have been shown to be enriched in men with non‐obstructive azoospermia implying a role for E2F1 in male‐factor infertility (Jorgez et al ., 2015). …”