Novel variants in helicase for meiosis 1 lead to male infertility due to non-obstructive azoospermia

Abstract

Background Non-obstructive azoospermia (NOA) is the most severe form of male infertility; more than half of the NOA patients are idiopathic. Although many NOA risk genes have been detected, the genetic factors for NOA in majority of the patients are unknown. In addition, it is difficult to retrieve sperm from these patients despite using the microsurgical testicular sperm extraction (microTESE) method. Therefore, we conducted this genetic study to identify the potential genetic factors responsible for NOA and investigate the sperm retrieval rate of microTESE for genetically deficient NOA patients. Methods Semen analyses, sex hormone testing, and testicular biopsy were performed to categorize the patients with NOA. The chromosome karyotypes and Y chromosome microdeletion analyses were used to exclude general genetic factors. Whole exome sequencing and Sanger sequencing were performed to identify potential genetic variants in 51 patients with NOA. Hematoxylin and eosin staining (H&E) and anti-phosphorylated H2AX were used to assess the histopathology of spermatogenesis. Quantitative real time-polymerase chain reaction, western blotting, and immunofluorescence were performed to verify the effects of gene variation on expression. Results We performed whole exome sequencing in 51 NOA patients and identified homozygous helicase for meiosis 1(HFM1) variants (NM_001017975: c.3490C > T: p.Q1164X; c.3470G > A: p.C1157Y) in two patients (3.9%, 2/51). Histopathology of the testis showed that spermatogenesis was completely blocked at metaphase in these two patients carrying the HFM1 homozygous variants. In comparison with unaffected controls, we found a significant reduction in the levels of HFM1 mRNA and protein expression in the testicular tissues from these two patients. The patients were also subjected to microTESE treatment, but the sperms could not be retrieved. Conclusions This study identified novel homozygous variants of HFM1 that are responsible for spermatogenic failure and NOA, and microTESE did not aid in retrieving sperms from these patients.

Non-invasive molecular biomarkers for predicting outcomes of micro-TESE in patients with idiopathic non-obstructive azoospermia

“…Although these patients underwent micro-TESE, no spermatozoa were retrieved in the testes (Ref. 55). In another study, we found that SSR was achieved by micro-TESE in a patient with INOA bearing a variant of the DMRT1 (OMIM: 602424) gene (Ref.…”

“…50) and TEX14 (OMIM: 605792) (Refs 51, 52). In parallel, several researchers explored the association between precise genetic diagnosis and SSR by micro-TESE in patients with INOA, aiming to propose genetic predictors for SSR prior to surgery (Refs 50, 53–55).…”

Novel MEIOB variants cause primary ovarian insufficiency and non-obstructive azoospermia

“…Nonobstructive azoospermia (NOA) is a serious male infertility disorder that accounts for more than 20% of the male infertility issues (Cioppi et al, 2021). NOA is typically associated with genetic defects, including Y chromosome microdeletions and spermatogenesis related gene mutations (TEX11, HFM1, and MEI1) (Yatsenko et al, 2015;Ben Khelifa et al, 2018;Tang et al, 2021). The causes of female infertility include premature ovarian insufficiency (POI), abnormal ovulation, tubal blockage and endometriosis (Sen et al, 2014).…”

“…POI is characterized by loss of normal ovarian function in women before 40 years of age (De Vos et al, 2010). It has been reported that a number of genes are responsible for POI, such as DNA damage repair relevant genes (FANCA, DMC1, MCM8, etc) (Desai et al, 2017;He et al, 2018;Yang et al, 2019) and hormone receptor genes (FSHR, LHCGR, etc) (He et al, 2019;Guo et al, 2021;Tang et al, 2021).…”

Pericentric inversion of chromosome 6 and male fertility problems

“…Genetic variation is one of the important causes of male infertility. Recently, Tang et al [ 2 ] reported that variants of homozygous helicase for meiosis 1 are responsible for spermatogenic failure. MLH3 single nucleotide polymorphisms in human populations can lead to male infertility [ 3 , 4 , 5 ].…”