Mutational screening of theNR5A1in azoospermia

Abstract

Nuclear receptor subfamily 5 group A member 1 (NR5A1) encodes a nuclear receptor that regulates transcription of multiple genes involved in adrenal and gonadal development, steroidogenesis and the reproductive axis. Human mutations in NR5A1were initially found in two 46, XY female patients suffering from severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in NR5A1 may also contribute to the male infertility aetiology. We have analysed the coding sequence of NR5A1 in a cohort of 90 well-characterised idiopathic Iranian azoospermic infertile men versus 112 fertile men. Heterozygous NR5A1 mutations were found in 2 of 90 (2.2%) of cases. These two patients harboured missense mutations within the hinge region (p.P97T) and ligand-binding domain (p.E237K) of the NR5A1 protein. In silico analysis of the mutations showed that founded mutations could be detrimental. In conclusion, findings of the current and previous studies suggest that mutations in the NR5A1 gene are not common in azoospermia, and male infertility and inclusion of NR5A1 mutation screening in the diagnostic workup of male infertility may seem unnecessary.

Mutational screening of NR5A1 gene encoding steroidogenic factor 1 in cryptorchidism and male factor infertility and functional analysis of seven undescribed mutations

“…Genetic causes might be involved in this phenomenon and are a typical example of the so-called testicular dysgenesis syndrome (26). NR5A1 has gained increasing attention in last year in this regard: it has been implicated in a broad range of phenotypes related to the urogenital system (6, 7); it regulates pivotal regulators of sex determination, testicular descent and differentiation, and steroidogenesis (9); and previous studies suggest its involvement in severe forms of male factor infertility (18)(19)(20). To clarify these aspects, we screened for NR5A1 mutations almost 1,000 well-characterized subjects, including children with cryptorchidism and adults with different semen phenotypes associated or not associated with a history of testicular maldescent.…”

“…Furthermore, according to the pivotal role of NR5A1 in regulating sex determination and differentiation, testicular descent, and reproduction (6,17), mutations in this gene have been recently associated in preliminary studies with severe forms of male factor infertility (18)(19)(20), with a frequency ranging from 0.7% (19), to 2.2% (20), to 3.5% (18).…”

NR5A1 mutations are not associated with male infertility in Indian men

“…Zare‐Abdollahi et al. () reported two novel mutations in men with idiopathic azoospermia of Iranian origin, one each in the hinge region and ligand‐binding domain of NR5A1 . Mutations in NR5A1 were also found in severe forms of spermatogenic failure with a history of cryptorchidism (Ferlin et al., ).…”

Glucose-6-phosphate dehydrogenase deficiency does not increase the susceptibility of sperm to oxidative stress induced by H2O2

“…A number of etiologies have been identified as possible causes of male infertility, including genetic factors, radiation, chemotherapy, infectious diseases, ejaculatory duct occlusion, varicocele, and erectile dysfunction [1234]. Reactive oxygen species (ROS) are chemically reactive molecules and are formed as a natural consequence of the usual metabolism of oxygen, ROS plays a major role in cell signaling and homeostasis.…”