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Can Non-Coding NR5A1 Gene Variants Explain Phenotypes of Disorders of Sex Development?

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Autor(es):
Fabbri-Scallet, Helena ; Werner, Ralf ; Guaragna, Mara S. ; de Andrade, Juliana G. R. ; Maciel-Guerra, Andrea T. ; Hornig, Nadine C. ; Hiort, Olaf ; Guerra-Junior, Gil ; de Mello, Maricilda P.
Número total de Autores: 9
Tipo de documento: Artigo Científico
Fonte: SEXUAL DEVELOPMENT; v. N/A, p. 9-pg., 2022-06-28.
Resumo

Introduction: NR5A1 is an essential transcription factor that regulates several target genes involved in reproduction and endocrine function. Pathogenic variants in this gene are responsible for a wide spectrum of disorders/differences of sex development (DSD). Methods: The molecular study involved Sanger sequencing, in vitro assays, and whole exome sequencing (WES). Results: Four variants were identified within the NR5A1 non-coding region in 3 patients with 46,XY DSD. In vitro analyses showed that promoter activity was affected in all cases. WES revealed variants in SRA1, WWOX, and WDR11 genes. Discussion/Conclusion: Evaluation of clinical and phenotypic significance of variants located in a non-coding region of a gene can be complex, and little is known regarding their association with DSD. Nevertheless, based on the important region for interaction with cofactors essential to promote appropriated sex development and on our in vitro results, it is feasible to say that an impact on gene expression can be expected and that this may be correlated with the DSD pathophysiology presented in our patients. Considering the number of cases that remain elusive after screening for the well-known DSD related genes, we emphasize the importance of a careful molecular analysis of NR5A1 non-coding region which is commonly neglected and might explain some idiopathic DSD cases. (AU)

Processo FAPESP: 13/05603-5 - Estudo funcional de novas variações nucleotídicas no gene NR5A1 em pacientes 46,XY com distúrbios da diferenciação do sexo
Beneficiário:Helena Fabbri Scallet
Modalidade de apoio: Bolsas no Brasil - Doutorado
Processo FAPESP: 13/24333-9 - Estudo funcional de novas variações nucleotídicas no gene NR5A1 em pacientes 46,XY com distúrbios da diferenciação do sexo
Beneficiário:Helena Fabbri Scallet
Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
Processo FAPESP: 18/19445-6 - Uso das técnicas de transcriptoma, exoma e expressão gênica para elucidar diferentes fenótipos de distúrbios da diferenciação do sexo em pacientes 46,xy
Beneficiário:Helena Fabbri Scallet
Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado