• PMID: 26139570
• Gene Name: DDX4
• Condition: Spermatogenic failure
• Association: Associated
• Mutation: DMRT1 (rs144122237, rs376518776, rs34946058, rs200423545)
• Population size: 599
• Population details: 599 (223 NOA patients, 376 controls )
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Spermatogenic failure

Rare double sex and mab-3-related transcription factor 1 regulatory variants in severe spermatogenic failure

Lima AC, Carvalho F, Gonçalves J, Fernandes S, Marques PI, Sousa M, Barros A, Seixas S, Amorim A, Conrad DF, Lopes AM.

The double sex and mab-3-related transcription factor 1 (DMRT1) gene has long been linked to sex-determining pathways across vertebrates and is known to play an essential role in gonadal development and maintenance of spermatogenesis in mice. In humans, the genomic region harboring the DMRT gene cluster has been implicated in disorders of sex development and recently DMRT1 deletions were shown to be associated with non-obstructive azoospermia (NOA). In this work, we have employed different methods to screen a cohort of Portuguese NOA patients for DMRT1 exonic insertions and deletions [by multiplex ligation probe assay (MLPA); n = 68] and point mutations (by Sanger sequencing; n = 155). We have found three novel patient-specific non-coding variants in heterozygosity that were absent from 357 geographically matched controls. One of these is a complex variant with a putative regulatory role (c.-223_-219CGAAA>T), located in the promoter region within a conserved sequence involved in Dmrt1 repression. Moreover, while DMRT1 domains are highly conserved across vertebrates and show reduced levels of diversity in human populations, two rare synonymous substitutions (rs376518776 and rs34946058) and two rare non-coding variants that potentially affect DMRT1 expression and splicing (rs144122237 and rs200423545) were overrepresented in patients when compared with 376 Portuguese controls (301 fertile and 75 normozoospermic). Overall our previous and present results suggest a role of changes in DMRT1 dosage in NOA potentially also through a process of gene misregulation, even though DMRT1 deleterious variants seem to be rare. CI - © 2015 American Society of Andrology and European Academy of Andrology. FAU - Lima, A C AU - Lima AC AD - Graduate Program in Areas of Basic and Applied Biology (GABBA), Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal. AD - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. AD - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal. AD - Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. FAU - Carvalho, F AU - Carvalho F AD - Department of Genetics, Faculty of Medicine of the University of Porto, Porto, Portugal. FAU - Gonçalves, J AU - Gonçalves J AD - Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, Lisboa, Portugal. FAU - Fernandes, S AU - Fernandes S AUID- ORCID: 0000-0003-1128-833X AD - Department of Genetics, Faculty of Medicine of the University of Porto, Porto, Portugal. FAU - Marques, P I AU - Marques PI AD - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. AD - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal. AD - Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal. FAU - Sousa, M AU - Sousa M AD - Laboratory of Cell Biology, UMIB, ICBAS, University of Porto, Porto, Portugal. FAU - Barros, A AU - Barros A AD - Department of Genetics, Faculty of Medicine of the University of Porto, Porto, Portugal. FAU - Seixas, S AU - Seixas S AD - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. AD - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal. FAU - Amorim, A AU - Amorim A AD - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. AD - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal. AD - Faculty of Sciences of the University of Porto, Porto, Portugal. FAU - Conrad, D F AU - Conrad DF AD - Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. AD - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.