Ubiquitin-specific protease (USP26) gene alterations associated with male infertility and recurrent pregnancy loss (RPL) in Iranian infertile patients

Abstract

Background and purpose The human X chromosome is enriched with testis-specific genes that may be crucial for male fertility. Mutations in USP26 gene have been proposed to be associated with male infertility. Moreover, the importance of the ubiquitin pathway during different stages of mammalian fertilization and even embryo development has been addressed. Some mutations and haplotypes on this gene have been proposed to be associated with male infertility. In this study, five different mutations on USP26 were investigated: 1737 G>A, 1090 C >T, 370-371ins ACA, 494 T>C and 1423 C>T. Methods The study included 166 infertile men with nonobstructive azoospermia, 72 male partners of couples who had previously experienced ≥3 clinical first trimester spontaneous abortions and 60 fertile men. Besides family history of reproduction, hormonal evaluation and semen analysis were performed. DNA was extracted from blood samples. PCR-SSCP, PCR-RFLP and PCR Product Cloning methods were used and resumed by sequencing to insure about the mutations. Moreover, USP26 gene expression was studied by Real-Time PCR after RNA extraction followed by cDNA synthesis from 24 testis biopsies in obstructive and non-obstructive azoospermia patients.Results The results indicate that there is a haplotype between three observed mutations in Iranian population include: 370-371insACA, 1423C>T and 494 T>C. This haplotype was seen in control group as well. Surprisingly, total frequency of mutations in men with history of idiopathic RPL and azoospermic cases were significantly higher than that of in control groups (p<0.05). Serum testosterone concentrations and testicular volume did not differ in the mutation positive group compared with the non-mutation group. About the USP26 gene expression, there is a significant difference between the expression levels of obstructive azoospermia, complete maturation arrest samples and SCO samples (P<0.05). Conclusions According to our results, the USP26 gene may play an important role in male reproduction. The alterations of this gene may be involved in male infertility and RPL in Iranian population and may negatively affect testicular function. Keywords Polymorphism . Male infertility . USP26Capsule In recent years, a lot of attention has been paid to genetic causes of male infertility. Moreover altered gene expression in spermatogenesis has been showed. Studies are mainly focusing on genes with a testis-specific expression pattern. Such genes which located on the sex chromosomes seem to be more important as men are hemizygous for these chromosomes. We analyzed the Ubiquitin Specific Protease 26 (USP26) gene for the presence of mutations in men with severe fertility problems.

Copy number variation profile in the placental and parental genomes of recurrent pregnancy loss families

“…Other members of the Ubiquitin-specific peptidase family have in fact been associated with male infertility and also RPL26.…”

Genetic Considerations in Recurrent Pregnancy Loss

“…Major groups of single gene defects that have been associated with pregnancy loss encompass musculoskeletal gene mutations including trinucleotide repeat disorders, genes involved in regulation of the immune system and implantation, thrombophilic gene mutations, and mutations in specific enzymes, including angiotensin-converting enzyme, ubiquitin-specific protease, and human alkaline phosphatase (Yang et al 2012a;Asadpor et al 2013;Wang et al 2013;Vatin et al 2014).…”

A Novel Missense Mutation in USP26 Gene Is Associated With Nonobstructive Azoospermia

“…12 Prior mutation screening has demonstrated that several USP26 gene variations were associated with male infertility, yet few functional studies have been performed. [13][14][15][16] No causative mutation in USP26 has been confirmed in infertile men.…”