NR5A1 Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations

Author(s)

Fabbri, Helena C. ; Ribeiro de Andrade, Juliana G. ; Maciel-Guerra, Andrea T. ; Guerra-Junior, Gil ; de Mello, Maricilda P.

• Document type: Journal article
• Source: SEXUAL DEVELOPMENT; v. 10, n. 4, p. 191-199, 2016.
• Web of Science Citations: 7

Abstract

Mutations in the NR5A1 gene, which encodes the steroidogenic factor 1 (SF1), are responsible for different phenotypes of disorders of sex development (DSD), such as bilateral anorchia and hypospadias. Furthermore, they can be associated with primary amenorrhea, premature ovarian failure, male infertility, adrenal tumors, and endometriosis. Direct sequencing of the 7 NR5A1 exons including similar to 1,000 bp of the 5'-upstream and 3'-downstream regions and all intron-exon boundaries was performed in patients with DSD. Three different in silico tools were used to assess the consequences of a splice site mutation. As a result, 3 novel NR5A1 mutations were identified in 3 patients with 46,XY partial gonadal dysgenesis: p.Lys38{*} and p.Leu80Trpfs{*}8 lead to premature translation termination codons within the SF1 DNA-binding domain, and the intronic nucleotide substitution c.1138+1G>T at the intron 6 donor splice site is considered to modify correct splicing. We assume that the anomalous mRNA produced as a result of plys38{*} and p.Leu80Trpfs{*}8 will be degraded by nonsense-mediated mRNA decay even before translation, leading to SF1 haploinsufficiency. The c.1138+1G>T mutation is expected to produce a truncated protein. Heterozygous SF1 loss-of-function mutations in these cases resulted in mild DSD manifestations, such as dysgenetic testes, spontaneous puberty, and preserved adrenal function. (C) 2016 S. Karger AG, Basel. (AU)

• FAPESP's process: 13/05603-5 - Functional analyses of new nucleotide variations in NR5A1 gene in patients 46,XY with disorders of sex development
• Grantee: Helena Fabbri Scallet
• Support Opportunities: Scholarships in Brazil - Doctorate