Novel mutation in USP26 associated with azoospermia in a Sertoli cell‐only syndrome patient

Abstract

BackgroundUbiquitin‐Specific Peptidase 26 (USP26), located on the X chromosome, encodes a deubiquitinating enzyme expressed mainly in testis, where it regulates protein turnover during spermatogenesis and modulates the ubiquitination levels of the Androgen Receptor (AR), and as a consequence, affects AR signaling.MethodsThe patient was thoroughly characterized clinically. He was genetically tested by chromosome analysis and whole exome sequencing (WES).ResultsThe patient was diagnosed with Sertoli cell‐only syndrome pattern (SCOS). The WES analysis revealed only the variation in USP26: causing p.P469S in a highly evolutionary conserved amino acid as the possible cause for SCOS. The literature search identified 34 single variations and 14 clusters of variations in USP26 that were associated with male infertility. Only one of the 22 variations and of one cluster of three mutations tested for ubiquitination activity was found as damaging. Only one out of six variations tested for effect on AR function was found as damaging. Thus, the association of USP26 with male fertility was questioned.ConclusionsThe finding in our patient and the discussion on the reviewed literature support a possible role for USP26 in male fertility.

A RNF12-USP26 amplification loop promotes germ cell specification and is disrupted in urogenital disorders

“…USP26 is specifically expressed in testes ( Figure S1) (Lin et al, 2011;Wang et al, 2001;Zhang et al, 2009) and is a key component within the RNF12-dependent germ cell specific transcriptional program that is disrupted in by RNF12/RLIM TOKAS variants. Interestingly, USP26 variants are implicated in azoospermia, including sertoli-cell only syndrome (A Paduch et al, 2005;Arafat et al, 2020;Stouffs et al, 2005), which prompts the hypothesis that USP26 variants may lead to deregulation of RNF12-dependent functions. USP26 variants are largely found clustered around a nuclear localisation sequence (NLS) and within the USP catalytic domain ( Figure 6A), with at least one implicated in disruption of catalytic activity (Liu et al, 2018).…”

Paternal USP26 mutations raise Klinefelter syndrome risk in the offspring of mice and humans

“…Here, we conducted a genetic analysis using whole‐exome sequencing (WES) in 108 unrelated KS patients and identified USP26 germline mutations that might be responsible for promoting paternal‐origin KS (Fig 1). USP26 has been associated with nonobstructive azoospermia (Xia et al, 2014; Luddi et al, 2016; Ma et al, 2016; Arafat et al, 2020), and Usp26 knockout mouse models only display a very slight impact on male fertility (Felipe‐Medina et al, 2019; Sakai et al, 2019; Tian et al, 2019). While we found that 2‐month‐old Usp26 −/ Y mice were indeed fertile, both the pregnancy rates and the litter sizes of Usp26 −/ Y mice were significantly reduced with increasing age (6‐month‐old mice; Fig 2A–D).…”

Novel Gene Regulation in Normal and Abnormal Spermatogenesis

“…Transcripts of RARA , RXRB , and RXRG are significantly reduced in patients with SCOS and maturation arrest (MA), but not in patients with spermatogenesis hypogenesis, suggesting that decreased levels of these genes are closely associated with the failure of SCOS and spermatogenesis MA [ 102 ]. New mutation in USP26 is related toSCOS patients [ 103 ]. Our team has found differential expression of LRP6 and Cyclin D1 in Sertoli cells between SCOS and OA patients with normal spermatogenesis [ 104 ].…”