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Publications

Journal Article Ppublish

PubMed: 39777458 DOI: 10.1093/hmg/ddae197

Diminished DNA binding affinity of DMRT1 caused by heterozygous DM domain mutations is a cause of male infertility.

Hum Mol Genet 34(6):481-491

Authors: Tihana Marić, Helen Castillo-Madeen, Monika Logara Klarić, Antun Barišić, Lovro Trgovec-Greif, Mark W Murphy, Anna-Grete Juchnewitsch, Kristiina Lillepea, Avirup Dutta, Lucija Žunić, Alexandra M Stendahl, Margus Punab, Kristjan Pomm, Daniel M Mendoza, Alexandra M Lopes, Ana Merkler Šorgić, Oliver Vugrek, Joao Gonçalves, Kristian Almstrup, Kenneth I Aston, Robert Belužić, Davor Ježek, Branimir Bertoša, Maris Laan, Ana Katušić Bojanac, Donald F Conrad, Maja Barbalić

Affiliations

  • Scientific Centre of Excellence for Reproductive and Regenerative Medicine, University of Zagreb School of Medicine, Šalata 2, Zagreb 10000, Croatia.
  • Department of Medical Biology, University of Zagreb School of Medicine, Šalata 2, Zagreb 10000, Croatia.
  • Division of Genetics, ONPRC & Oregon Health & Science University, 505 N.W. 185th Avenue, Beaverton, OR, USA.
  • Genom Ltd. Ilica 190, Zagreb 10000, Croatia.
  • Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102A, Zagreb 10000, Croatia.
  • Ruđer Bošković Institute, Bijenička Cesta 54, Zagreb 10000, Croatia.
  • Department of Genetics, Cell Biology, and Development, University of Minnesota, 321 Church St. SE, Minneapolis, MN, USA.
  • Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila tn 19, Tartu, Estonia.
  • Andrology Clinic, Tartu University Hospital, Ludvig Puusepa 8, Tartu, Estonia.
  • Andrology Department, Universitat Autònoma de Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain.
  • University of Porto, Praça de Gomes Teixeira, 4099-002 Porto, Portugal.
  • University Hospital Zagreb, Ulica Mije Kišpatića 12, Zagreb 10000, Croatia.
  • Departamento de Genética Humana, INSA, Av. Padre Cruz, 1649-016 Lisbon, Portugal.
  • Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark.
  • Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen, Denmark.
  • Andrology and IVF Laboratory, University of Utah School of Medicine, 675 Arapeen Dr 201 Suite 201, Salt Lake City, UT, USA.
  • Faculty of Science, University of Split, Ruđera Bošković 33, Split 21000, Croatia.

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.

MeSH

Genes, Genetics, Infertility, Infertility, Male, Cytogenetics, Spermatozoa, Mutation