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

摘要: Summary The double sex and mab-3-related transcription factor 1 (DMRT1) gene has long been linked to sex-determining pathways across vertebrates is known play an essential role in gonadal development maintenance of spermatogenesis mice. In humans, the genomic region harboring DMRT cluster implicated disorders recently DMRT1 deletions were shown be associated with non-obstructive azoospermia (NOA). this work, we have employed different methods screen a cohort Portuguese NOA patients for exonic insertions [by multiplex ligation probe assay (MLPA); n = 68] point mutations (by Sanger sequencing; n = 155). We found three novel patient-specific non-coding variants heterozygosity that absent from 357 geographically matched controls. One these complex variant putative regulatory (c.-223_-219CGAAA>T), located promoter within conserved sequence involved Dmrt1 repression. Moreover, while domains are highly show reduced levels diversity human populations, two rare synonymous substitutions (rs376518776 rs34946058) potentially affect expression splicing (rs144122237 rs200423545) overrepresented when compared 376 controls (301 fertile 75 normozoospermic). Overall our previous present results suggest changes dosage also through process misregulation, even though deleterious seem rare.