Diminished DNA binding affinity of DMRT1 caused by heterozygous DM domain mutations is a cause of male infertility
The most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that w...
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| Vydáno v: | Human molecular genetics Ročník 34; číslo 6; s. 481 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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England
07.03.2025
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| ISSN: | 1460-2083, 1460-2083 |
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| Abstract | The most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that was further assessed by the EMSA assay and molecular dynamic simulations. We additionally screened for DMRT1 mutations in 1940 infertile men diagnosed with spermatogenic failure, 644 normozoospermic controls, and 105 females with primary ovarian insufficiency (POI) recruited to the GEnetics of Male INfertility Initiative (GEMINI) or Estonian Andrology (ESTAND) cohorts. DMRT1 p.Pro74Leu (chr9:g.842059C > T) variant was detected in infertile brothers in the highly conserved position within the DNA binding DM domain of the protein. EMSA assay showed reduced DNA binding of DMRT1P74L and molecular dynamic simulations showed differences in structural and dynamical properties between the wild type protein and DMRT1P74L. Plausible disease-causing DMRT1 variants were only identified in infertile men (13/1940; 0.67%), and none in 639 fertile controls. Burden testing showed an excess of rare deleterious DM domain mutations in the infertility cohort compared to gnomAD v.4.0 population-based controls (Fisher's exact test, p = 1.44 x 10-5). Three rare deleterious variants in DMRT1 were found in 104 cases of POI. The findings of this study strengthen the evidence of DMRT1 variants being a causal factor for male infertility and provide the distribution of likely pathogenic variants across the gene. This is also the first study to suggest that DMRT1 variants may also be linked to POI. |
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| AbstractList | The most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that was further assessed by the EMSA assay and molecular dynamic simulations. We additionally screened for DMRT1 mutations in 1940 infertile men diagnosed with spermatogenic failure, 644 normozoospermic controls, and 105 females with primary ovarian insufficiency (POI) recruited to the GEnetics of Male INfertility Initiative (GEMINI) or Estonian Andrology (ESTAND) cohorts. DMRT1 p.Pro74Leu (chr9:g.842059C > T) variant was detected in infertile brothers in the highly conserved position within the DNA binding DM domain of the protein. EMSA assay showed reduced DNA binding of DMRT1P74L and molecular dynamic simulations showed differences in structural and dynamical properties between the wild type protein and DMRT1P74L. Plausible disease-causing DMRT1 variants were only identified in infertile men (13/1940; 0.67%), and none in 639 fertile controls. Burden testing showed an excess of rare deleterious DM domain mutations in the infertility cohort compared to gnomAD v.4.0 population-based controls (Fisher's exact test, p = 1.44 x 10-5). Three rare deleterious variants in DMRT1 were found in 104 cases of POI. The findings of this study strengthen the evidence of DMRT1 variants being a causal factor for male infertility and provide the distribution of likely pathogenic variants across the gene. This is also the first study to suggest that DMRT1 variants may also be linked to POI. The most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that was further assessed by the EMSA assay and molecular dynamic simulations. We additionally screened for DMRT1 mutations in 1940 infertile men diagnosed with spermatogenic failure, 644 normozoospermic controls, and 105 females with primary ovarian insufficiency (POI) recruited to the GEnetics of Male INfertility Initiative (GEMINI) or Estonian Andrology (ESTAND) cohorts. DMRT1 p.Pro74Leu (chr9:g.842059C > T) variant was detected in infertile brothers in the highly conserved position within the DNA binding DM domain of the protein. EMSA assay showed reduced DNA binding of DMRT1P74L and molecular dynamic simulations showed differences in structural and dynamical properties between the wild type protein and DMRT1P74L. Plausible disease-causing DMRT1 variants were only identified in infertile men (13/1940; 0.67%), and none in 639 fertile controls. Burden testing showed an excess of rare deleterious DM domain mutations in the infertility cohort compared to gnomAD v.4.0 population-based controls (Fisher's exact test, p = 1.44 x 10-5). Three rare deleterious variants in DMRT1 were found in 104 cases of POI. The findings of this study strengthen the evidence of DMRT1 variants being a causal factor for male infertility and provide the distribution of likely pathogenic variants across the gene. This is also the first study to suggest that DMRT1 variants may also be linked to POI.The most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that was further assessed by the EMSA assay and molecular dynamic simulations. We additionally screened for DMRT1 mutations in 1940 infertile men diagnosed with spermatogenic failure, 644 normozoospermic controls, and 105 females with primary ovarian insufficiency (POI) recruited to the GEnetics of Male INfertility Initiative (GEMINI) or Estonian Andrology (ESTAND) cohorts. DMRT1 p.Pro74Leu (chr9:g.842059C > T) variant was detected in infertile brothers in the highly conserved position within the DNA binding DM domain of the protein. EMSA assay showed reduced DNA binding of DMRT1P74L and molecular dynamic simulations showed differences in structural and dynamical properties between the wild type protein and DMRT1P74L. Plausible disease-causing DMRT1 variants were only identified in infertile men (13/1940; 0.67%), and none in 639 fertile controls. Burden testing showed an excess of rare deleterious DM domain mutations in the infertility cohort compared to gnomAD v.4.0 population-based controls (Fisher's exact test, p = 1.44 x 10-5). Three rare deleterious variants in DMRT1 were found in 104 cases of POI. The findings of this study strengthen the evidence of DMRT1 variants being a causal factor for male infertility and provide the distribution of likely pathogenic variants across the gene. This is also the first study to suggest that DMRT1 variants may also be linked to POI. |
| Author | Pomm, Kristjan Conrad, Donald F Belužić, Robert Almstrup, Kristian Bojanac, Ana Katušić Vugrek, Oliver Stendahl, Alexandra M Šorgić, Ana Merkler Bertoša, Branimir Lillepea, Kristiina Barbalić, Maja Mendoza, Daniel M Barišić, Antun Castillo-Madeen, Helen Punab, Margus Žunić, Lucija Klarić, Monika Logara Laan, Maris Murphy, Mark W Lopes, Alexandra M Gonçalves, Joao Aston, Kenneth I Dutta, Avirup Marić, Tihana Trgovec-Greif, Lovro Juchnewitsch, Anna-Grete Ježek, Davor |
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Padre Cruz, 1649-016 Lisbon, Portugal – sequence: 19 givenname: Kristian surname: Almstrup fullname: Almstrup, Kristian organization: Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, Denmark – sequence: 20 givenname: Kenneth I surname: Aston fullname: Aston, Kenneth I organization: Andrology and IVF Laboratory, University of Utah School of Medicine, 675 Arapeen Dr 201 Suite 201, Salt Lake City, UT, USA – sequence: 21 givenname: Robert surname: Belužić fullname: Belužić, Robert organization: Ruđer Bošković Institute, Bijenička Cesta 54, Zagreb 10000, Croatia – sequence: 22 givenname: Davor surname: Ježek fullname: Ježek, Davor organization: University Hospital Zagreb, Ulica Mije Kišpatića 12, Zagreb 10000, Croatia – sequence: 23 givenname: Branimir surname: Bertoša fullname: Bertoša, Branimir organization: Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, Zagreb 10000, Croatia – sequence: 24 givenname: Maris surname: Laan fullname: Laan, Maris organization: Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila tn 19, Tartu, Estonia – sequence: 25 givenname: Ana Katušić surname: Bojanac fullname: Bojanac, Ana Katušić organization: Department of Medical Biology, University of Zagreb School of Medicine, Šalata 2, Zagreb 10000, Croatia – sequence: 26 givenname: Donald F surname: Conrad fullname: Conrad, Donald F organization: Division of Genetics, ONPRC & Oregon Health & Science University, 505 N.W. 185th Avenue, Beaverton, OR, USA – sequence: 27 givenname: Maja orcidid: 0000-0001-8914-1691 surname: Barbalić fullname: Barbalić, Maja organization: Faculty of Science, University of Split, Ruđera Bošković 33, Split 21000, Croatia |
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| Keywords | exome sequencing genetics DMRT1 infertility |
| Language | English |
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| Snippet | The most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome... |
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| SubjectTerms | Adult Azoospermia - genetics Azoospermia - pathology DNA - genetics DNA - metabolism Exome Sequencing Female Genetic Predisposition to Disease Heterozygote Humans Infertility, Male - genetics Infertility, Male - metabolism Male Molecular Dynamics Simulation Mutation Primary Ovarian Insufficiency - genetics Protein Binding Protein Domains Transcription Factors - chemistry Transcription Factors - genetics Transcription Factors - metabolism |
| Title | Diminished DNA binding affinity of DMRT1 caused by heterozygous DM domain mutations is a cause of male infertility |
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