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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Human molecular genetics Jg. 34; H. 6; S. 481
Hauptverfasser: Marić, Tihana, Castillo-Madeen, Helen, Klarić, Monika Logara, Barišić, Antun, Trgovec-Greif, Lovro, Murphy, Mark W, Juchnewitsch, Anna-Grete, Lillepea, Kristiina, Dutta, Avirup, Žunić, Lucija, Stendahl, Alexandra M, Punab, Margus, Pomm, Kristjan, Mendoza, Daniel M, Lopes, Alexandra M, Šorgić, Ana Merkler, Vugrek, Oliver, Gonçalves, Joao, Almstrup, Kristian, Aston, Kenneth I, Belužić, Robert, Ježek, Davor, Bertoša, Branimir, Laan, Maris, Bojanac, Ana Katušić, Conrad, Donald F, Barbalić, Maja
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England 07.03.2025
Schlagworte:
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
exome sequencing
genetics
DMRT1
infertility
ISSN:1460-2083, 1460-2083
Online-Zugang:Weitere Angaben
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1460-2083
1460-2083
DOI:10.1093/hmg/ddae197