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Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility
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 cruci...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
PeerJ Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8944341/ https://www.ncbi.nlm.nih.gov/pubmed/35341049 http://dx.doi.org/10.7717/peerj.12947 |
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author | Gerlevik, Umut Ergoren, Mahmut Cerkez Sezerman, Osman Uğur Temel, Sehime Gulsun |
author_facet | Gerlevik, Umut Ergoren, Mahmut Cerkez Sezerman, Osman Uğur Temel, Sehime Gulsun |
author_sort | Gerlevik, Umut |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8944341 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | PeerJ Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89443412022-03-25 Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility Gerlevik, Umut Ergoren, Mahmut Cerkez Sezerman, Osman Uğur Temel, Sehime Gulsun PeerJ Bioinformatics 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. PeerJ Inc. 2022-03-21 /pmc/articles/PMC8944341/ /pubmed/35341049 http://dx.doi.org/10.7717/peerj.12947 Text en © 2022 Gerlevik et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited. |
spellingShingle | Bioinformatics Gerlevik, Umut Ergoren, Mahmut Cerkez Sezerman, Osman Uğur Temel, Sehime Gulsun Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility |
title | Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility |
title_full | Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility |
title_fullStr | Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility |
title_full_unstemmed | Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility |
title_short | Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility |
title_sort | structural analysis of m1ap variants associated with severely impaired spermatogenesis causing male infertility |
topic | Bioinformatics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8944341/ https://www.ncbi.nlm.nih.gov/pubmed/35341049 http://dx.doi.org/10.7717/peerj.12947 |
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