ESPE Abstracts

Background: Disorders of sex development (DSD) characterize incomplete or disorganized genital or gonadal development. One in 4500 births requires genetic and endocrine studies due to abnormal external genitalia or gonadal dysgenesis and only 50% of the cases receive a definitive diagnosis. There are several genes that participate in both sex determination and differentiation processes. Mutations in NR5A1 gene, which encoding SF1, a transcription factor, are responsible for different phenotypes of DSD and can be also associated with hypospadias, anorchia, male infertility, female primary ovarian insufficiency and, in some cases, with adrenal tumors and endometriosis.

Objective and hypotheses: Evaluate NR5A1 gene in 66 patients with 46,XY DSD.

Method: Direct sequencing of the seven exons of NR5A1 gene, including the promoter region and intron/exon boundaries and 3′UTR was performed.

Results: The study reveled three novel NR5A1 gene mutations. Two of them had been identified in patients with 46,XY partial gonadal disgenesis: p.Lys38* within DNA-binding domain and p.Lys1187Argfs*34 within ligand-binding domain. The third is the p.Leu80Trpfs*8 within DNA-binding domain that was identified in an idiopathic 46,XY DSD case. Both p.Lys38* and p.Leu80Trpfs*8 located in the DNA binding domain of SF1 create a stop codon in the beginning of the protein. Assuming that the mRNA will be degraded by nonsense mRNA decay even before the translation, those mutations certainly are associated with DSD phenotypes. The p.Lys1187Argfs*34, localized within the ligand binding domain of SF1, is a frameshift mutation leading also to a stop codon, however in this case it is located at the end of the protein; for this reason, functional studies will be done to investigate how it influences SF1 transactivation activities.

Conclusion: Those finds highlights the important role of SF1 in sexual development and demonstrate the significance of NR5A1 molecular analyzes in cases of patients with disorders of sex development.