Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility

PeerJ

article

Umut Gerlevik¹  Mahmut Cerkez Ergoren³  Osman Uğur Sezerman¹  Sehime Gulsun Temel⁶ 

[1] Department of Biostatistics and Bioinformatics, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University;Department of Biochemistry, University of Oxford;Department of Medical Genetics, Faculty of Medicine, Near East University;DESAM Institute, Near East University;Department of Biostatistics and Medical Informatics, School of Medicine, Acibadem Mehmet Ali Aydinlar University;Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University;Department of Histology & Embryology, Faculty of Medicine, Bursa Uludag University;Department of Translational Medicine, Health Sciences Institute, Bursa Uludag University

关键词: Molecular modelling;    Molecular dynamics simulations;    Male infertility;    Meisos 1-associated protein (M1AP);    Non-obstructive azoospermia (NOA);    Cryptozoospermia;    Variant effect on protein structure;   

DOI  :  10.7717/peerj.12947

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

Background Impaired meiosis can result in absence of sperm in the seminal fluid. This condition, namely non-obstructive azoospermia (NOA), is one of the reasons of male infertility. Despite the low number of studies on meiosis 1-associated protein (M1AP) in the literature, M1AP is known to be crucial for spermatogenesis. Recently, seven variants (five missense, one frameshift, one splice-site) have been reported in the M1AP gene as associated with NOA, cryptozoospermia and oligozoospermia in two separate studies. However, all missense variants were evaluated as variant of uncertain significance by these studies. Therefore, we aimed to analyze their structural impacts on the M1AP protein that could lead to NOA. Methods We firstly performed an evolutionary conservation analysis for the variant positions. Afterwards, a comprehensive molecular modelling study was performed for the M1AP structure. By utilizing this model, protein dynamics were sampled for the wild-type and variants by performing molecular dynamics (MD) simulations. Results All variant positions are highly conserved, indicating that they are potentially important for function. In MD simulations, none of the variants led to a general misfolding or loss of stability in the protein structure, but they did cause severe modifications in the conformational dynamics of M1AP, particularly through changes in local interactions affecting flexibility, hinge and secondary structure. Conclusions Due to critical perturbations in protein dynamics, we propose that these variants may cause NOA by affecting important interactions regulating meiosis, particularly in wild-type M1AP deficiency since the variants are reported to be homozygous or bi-allelic in the infertile individuals. Our results provided reasonable insights about the M1AP structure and the effects of the variants to the structure and dynamics, which should be further investigated by experimental studies to validate.

【 授权许可】

CC BY