Computational Analysis of the Potential Impact of MTC Complex Missenses SNPs Associated with Male Infertility
Meiotic chromosomes endure rapid prophase movements that ease the formation of interhomologue recombination intermediates that drive synapsis, crossing over, and segregation process. To generate these fast moves, the meiotic telomere complex (MTC) enables telomere-inner nuclear membrane attachment d...
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| description | Meiotic chromosomes endure rapid prophase movements that ease the formation of interhomologue recombination intermediates that drive synapsis, crossing over, and segregation process. To generate these fast moves, the meiotic telomere complex (MTC) enables telomere-inner nuclear membrane attachment during meiotic prophase I and transfers cytoskeletal signals via another complex: the LINC complex. Furthermore, disruption or mutations of any of the MTC genes (TERB1, TERB2, and MAJIN) alters telomere association with the nuclear envelope leading to impairment of homologous pairing and synapsis, a meiotic arrest, and consequently to male infertility. To decipher the effect of TERB1, TERB2, and MAJIN missense mutations on protein structure, stability, and function, different bioinformatic tools were used in this study including VEP, Mutabind2, Haddock, Prodigy, Ligplot, ConSurf, DUET and MusiteDeep. In total, thirty mutations were predicted to be deleterious using VEP web server: seventeen for TERB1, eleven for TERB2, and two for MAJIN. All these single nucleotide polymorphisms were further analyzed and only 11 SNPs (W8R, G25R, P649A, I624T, C618R, F607V, S604G, C592Y, C592R, G187W, and R53C) were found to be the most damaging by at least six software tools and exert deleterious effect on the TERB1, TERB2, and MAJIN protein structures and likely functions. They revealed high conservation, less stability, and having a role in posttranslational modifications. This in silico approach provides information to gain further insights about variants that might affect stability, change binding affinity, and edit protein-protein interactions to facilitate their identification and functional characterization associated with male infertility. |
| doi_str_mv | 10.1155/2022/1664825 |
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To generate these fast moves, the meiotic telomere complex (MTC) enables telomere-inner nuclear membrane attachment during meiotic prophase I and transfers cytoskeletal signals via another complex: the LINC complex. Furthermore, disruption or mutations of any of the MTC genes (TERB1, TERB2, and MAJIN) alters telomere association with the nuclear envelope leading to impairment of homologous pairing and synapsis, a meiotic arrest, and consequently to male infertility. To decipher the effect of TERB1, TERB2, and MAJIN missense mutations on protein structure, stability, and function, different bioinformatic tools were used in this study including VEP, Mutabind2, Haddock, Prodigy, Ligplot, ConSurf, DUET and MusiteDeep. In total, thirty mutations were predicted to be deleterious using VEP web server: seventeen for TERB1, eleven for TERB2, and two for MAJIN. All these single nucleotide polymorphisms were further analyzed and only 11 SNPs (W8R, G25R, P649A, I624T, C618R, F607V, S604G, C592Y, C592R, G187W, and R53C) were found to be the most damaging by at least six software tools and exert deleterious effect on the TERB1, TERB2, and MAJIN protein structures and likely functions. They revealed high conservation, less stability, and having a role in posttranslational modifications. This in silico approach provides information to gain further insights about variants that might affect stability, change binding affinity, and edit protein-protein interactions to facilitate their identification and functional characterization associated with male infertility.</description><identifier>ISSN: 2314-6133</identifier><identifier>EISSN: 2314-6141</identifier><identifier>DOI: 10.1155/2022/1664825</identifier><identifier>PMID: 35342767</identifier><language>eng</language><publisher>United States: Hindawi</publisher><subject>Amino acids ; Binding sites ; Bioinformatics ; Biomedical research ; Cell Cycle Proteins - genetics ; Cell division ; Chromosomes ; Computer applications ; Cytoskeleton ; Genetic aspects ; Genetic research ; Health aspects ; Homology ; Humans ; Infertility ; Infertility, Male ; Infertility, Male - genetics ; Intermediates ; Male ; Males ; Mammals ; Meiosis ; Meiosis - genetics ; Metaphase ; Missense mutation ; Mutation ; Nucleotides ; Polymorphism, Single Nucleotide - genetics ; Prophase ; Protein interaction ; Protein structure ; Proteins ; Recombination ; Risk factors ; Segregation process ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Software ; Software development tools ; Structural stability ; Structure ; Structure-function relationships ; Telomerase ; Telomere - metabolism ; Telomere-Binding Proteins - genetics ; Telomeres</subject><ispartof>BioMed research international, 2022, Vol.2022 (1), p.1664825-1664825</ispartof><rights>Copyright © 2022 Houda Harmak et al.</rights><rights>COPYRIGHT 2022 John Wiley & Sons, Inc.</rights><rights>Copyright © 2022 Houda Harmak et al. This is an open access article distributed under the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. https://creativecommons.org/licenses/by/4.0</rights><rights>Copyright © 2022 Houda Harmak et al. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-1a2c7dff267075818b9f23d88260bac1da1f06bae628d893d8d5463b1e5f10ae3</citedby><cites>FETCH-LOGICAL-c406t-1a2c7dff267075818b9f23d88260bac1da1f06bae628d893d8d5463b1e5f10ae3</cites><orcidid>0000-0002-6239-0281 ; 0000-0002-9338-6744 ; 0000-0002-1153-9170 ; 0000-0002-5252-0257</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8956405/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8956405/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,4010,27900,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35342767$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Harrison, Paul</contributor><contributor>Paul Harrison</contributor><creatorcontrib>Harmak, Houda</creatorcontrib><creatorcontrib>Charoute, Hicham</creatorcontrib><creatorcontrib>Redouane, Salaheddine</creatorcontrib><creatorcontrib>Filali, Ouafaa Aniq</creatorcontrib><creatorcontrib>Barakat, Abdelhamid</creatorcontrib><creatorcontrib>Rouba, Hassan</creatorcontrib><title>Computational Analysis of the Potential Impact of MTC Complex Missenses SNPs Associated with Male Infertility</title><title>BioMed research international</title><addtitle>Biomed Res Int</addtitle><description>Meiotic chromosomes endure rapid prophase movements that ease the formation of interhomologue recombination intermediates that drive synapsis, crossing over, and segregation process. To generate these fast moves, the meiotic telomere complex (MTC) enables telomere-inner nuclear membrane attachment during meiotic prophase I and transfers cytoskeletal signals via another complex: the LINC complex. Furthermore, disruption or mutations of any of the MTC genes (TERB1, TERB2, and MAJIN) alters telomere association with the nuclear envelope leading to impairment of homologous pairing and synapsis, a meiotic arrest, and consequently to male infertility. To decipher the effect of TERB1, TERB2, and MAJIN missense mutations on protein structure, stability, and function, different bioinformatic tools were used in this study including VEP, Mutabind2, Haddock, Prodigy, Ligplot, ConSurf, DUET and MusiteDeep. In total, thirty mutations were predicted to be deleterious using VEP web server: seventeen for TERB1, eleven for TERB2, and two for MAJIN. 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This in silico approach provides information to gain further insights about variants that might affect stability, change binding affinity, and edit protein-protein interactions to facilitate their identification and functional characterization associated with male infertility.</description><subject>Amino acids</subject><subject>Binding sites</subject><subject>Bioinformatics</subject><subject>Biomedical research</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Cell division</subject><subject>Chromosomes</subject><subject>Computer applications</subject><subject>Cytoskeleton</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Health aspects</subject><subject>Homology</subject><subject>Humans</subject><subject>Infertility</subject><subject>Infertility, Male</subject><subject>Infertility, Male - genetics</subject><subject>Intermediates</subject><subject>Male</subject><subject>Males</subject><subject>Mammals</subject><subject>Meiosis</subject><subject>Meiosis - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>BioMed research international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Harmak, Houda</au><au>Charoute, Hicham</au><au>Redouane, Salaheddine</au><au>Filali, Ouafaa Aniq</au><au>Barakat, Abdelhamid</au><au>Rouba, Hassan</au><au>Harrison, Paul</au><au>Paul Harrison</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Computational Analysis of the Potential Impact of MTC Complex Missenses SNPs Associated with Male Infertility</atitle><jtitle>BioMed research international</jtitle><addtitle>Biomed Res Int</addtitle><date>2022</date><risdate>2022</risdate><volume>2022</volume><issue>1</issue><spage>1664825</spage><epage>1664825</epage><pages>1664825-1664825</pages><issn>2314-6133</issn><eissn>2314-6141</eissn><abstract>Meiotic chromosomes endure rapid prophase movements that ease the formation of interhomologue recombination intermediates that drive synapsis, crossing over, and segregation process. To generate these fast moves, the meiotic telomere complex (MTC) enables telomere-inner nuclear membrane attachment during meiotic prophase I and transfers cytoskeletal signals via another complex: the LINC complex. Furthermore, disruption or mutations of any of the MTC genes (TERB1, TERB2, and MAJIN) alters telomere association with the nuclear envelope leading to impairment of homologous pairing and synapsis, a meiotic arrest, and consequently to male infertility. To decipher the effect of TERB1, TERB2, and MAJIN missense mutations on protein structure, stability, and function, different bioinformatic tools were used in this study including VEP, Mutabind2, Haddock, Prodigy, Ligplot, ConSurf, DUET and MusiteDeep. In total, thirty mutations were predicted to be deleterious using VEP web server: seventeen for TERB1, eleven for TERB2, and two for MAJIN. All these single nucleotide polymorphisms were further analyzed and only 11 SNPs (W8R, G25R, P649A, I624T, C618R, F607V, S604G, C592Y, C592R, G187W, and R53C) were found to be the most damaging by at least six software tools and exert deleterious effect on the TERB1, TERB2, and MAJIN protein structures and likely functions. They revealed high conservation, less stability, and having a role in posttranslational modifications. This in silico approach provides information to gain further insights about variants that might affect stability, change binding affinity, and edit protein-protein interactions to facilitate their identification and functional characterization associated with male infertility.</abstract><cop>United States</cop><pub>Hindawi</pub><pmid>35342767</pmid><doi>10.1155/2022/1664825</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-6239-0281</orcidid><orcidid>https://orcid.org/0000-0002-9338-6744</orcidid><orcidid>https://orcid.org/0000-0002-1153-9170</orcidid><orcidid>https://orcid.org/0000-0002-5252-0257</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Amino acids Binding sites Bioinformatics Biomedical research Cell Cycle Proteins - genetics Cell division Chromosomes Computer applications Cytoskeleton Genetic aspects Genetic research Health aspects Homology Humans Infertility Infertility, Male Infertility, Male - genetics Intermediates Male Males Mammals Meiosis Meiosis - genetics Metaphase Missense mutation Mutation Nucleotides Polymorphism, Single Nucleotide - genetics Prophase Protein interaction Protein structure Proteins Recombination Risk factors Segregation process Single nucleotide polymorphisms Single-nucleotide polymorphism Software Software development tools Structural stability Structure Structure-function relationships Telomerase Telomere - metabolism Telomere-Binding Proteins - genetics Telomeres |
| title | Computational Analysis of the Potential Impact of MTC Complex Missenses SNPs Associated with Male Infertility |
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