Abstract
BackgroundNon-obstructive azoospermia (NOA) is one of the most severe type in male infertility, and the genetic causes of NOA with meiotic arrest remain elusive.MethodsFour Chinese families with NOA participated in the study. We performed whole-exome sequencing (WES) for the four NOA-affected patients in four pedigrees. The candidate causative gene was further verified by Sanger sequencing. Hematoxylin and eosin staining (H&E) and immunohistochemistry (IHC) were carried out to evaluate the stage of spermatogenesis arrested in the patients with NOA.ResultsWe identified two novel homozygous frameshift mutations of MSH4 and two novel compound heterozygous variants in MSH4 in four pedigrees with NOA. Homozygous loss of function (LoF) variants in MSH4 was identified in the NOA-affected patient (P9359) in a consanguineous Chinese family (NM_002440.4: c.805_812del: p.V269Qfs*15) and one patient with NOA (P21504) in another Chinese family (NM_002440.4: c.2220_2223del:p.K741Rfs*2). Also, compound heterozygous variants in MSH4 were identified in two NOA-affected siblings (P9517 and P9517B) (NM_002440.4: c.G1950A: p.W650X and c.2179delG: p.D727Mfs*11), and the patient with NOA (P9540) (NM_002440.4: c.G244A: p.G82S and c.670delT: p.L224Cfs*3). Histological analysis demonstrated lack of spermatozoa in seminiferous tubules of all patients and IHC showed the spermatogenesis arrested at the meiotic prophase I stage. Consistent with the autosomal recessive mode of inheritance, all of these mutations were inherited from heterozygous parental carriers.ConclusionsWe identified that six novel mutations in MSH4 responsible for meiotic arrest and NOA. And these results provide researchers with a new insight to understand the genetic etiology of NOA and to identify new loci for genetic counselling of NOA.
Highlights
Male infertility is a multifactorial heterogeneous pathological condition, affecting ∼7% of male general population
Full list of author information is available at the end of the article
Non-obstructive azoospermia (NOA) displays germ cell absence or reduction owing to the testicular atrophy, and NOA usually results from Y chromosome microdeletion, chromosome abnormalities, hypogonadism, varicocele, testicular tumor, and improper drug administration
Summary
Male infertility is a multifactorial heterogeneous pathological condition, affecting ∼7% of male general population. Non-obstructive azoospermia (NOA) is one of the most severe male reproductive diseases, which occurs in ∼1% of men [1]. The defect of meiosis could lead to meiotic arrest and NOA. During the meiosis prophase I, homologous recombination resulted in crossover (CO) formation in the context of the synaptonemal complex (SC). It has been demonstrated that loss of Msh or Msh results in defects of prophase I progression in mice, with almost complete failure of homologous synapsis, and cell death prior to pachynema [9,10,11]. Many other types of mutation in MSH4 which were associated with NOA remain to be elucidated. Non-obstructive azoospermia (NOA) is one of the most severe type in male infertility, and the genetic causes of NOA with meiotic arrest remain elusive
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