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A novel homozygous mutation in the meiotic gene MSH4 leading to male infertility due to non-obstructive azoospermia

ABSTRACT: Non-obstructive azoospermia (NOA) is the most severe form of male infertility. Although some causes have been established, including genetic causes, the etiology in most cases remains idiopathic. Mutations in MSH4 (OMIM: 602105), an important gene involved in meiosis, may be related to female infertility due to primary ovarian insufficiency (POI) and male NOA. Here, we report a novel homozygous stop-gain mutation of MSH4 associated with NOA. Whole exome sequencing (WES) and bioinformatic analysis were performed in a patient with NOA from a consanguineous family (F1 II-1). A rare homozygous MSH4 stop-gain mutation (c.1552C>T:p.Q518X) was observed in the patient, and his parents were heterozygous carriers, as verified by Sanger sequencing. Testicular biopsy and hematoxylin and eosin staining of testicular tissue suggested meiotic arrest (MA), and no sperm were observed. MSH4 was detected in other 50 separate cases with same pathological results of MA using the same procedures, but only one heterozygous mutation was observed. Subsequent real-time quantitative polymerase chain reaction and immunohistochemistry were performed to examine mRNA expression levels and the localization of the MSH4 protein in the testicular tissue. Furthermore, the expression of MSH4 mRNA was significantly decreased compared with normal control. MSH4 protein was highly expressed in spermatocytes in the seminiferous tubules of the normal control, while no obvious expression was observed in F1 II-1. In this present study, MSH4 was identified as a candidate gene of male infertility causing NOA. A novel mutation of MSH4 (c.1552C>T:p.Q518X) is associated with the MA phenotype during spermatogenesis.

SUBMITTER: Tang D

PROVIDER: S-EPMC7791528 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundNon-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.MethodsSemen 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.ResultsWe 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.ConclusionsThis 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.

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A novel homozygous mutation in the meiotic gene MSH4 leading to male infertility due to non-obstructive azoospermia

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