<b><i>NR5A1</i></b> Loss-of-Function Mutations Lead to 46,XY Partial Gonadal Dysgenesis Phenotype: Report of Three Novel Mutations

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 ∼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 p.Lys38* 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.

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

“…Progressive androgen production and virilization in adolescence has been observed in several XY patients with NR5A1 mutations, in contrast to the severe undervirilized external genitalia found in most patients (Cools et al, 2012; Gabriel Ribeiro de Andrade et al, 2014; Tantawy et al, 2014; Fabbri et al, 2016). The almost normal testosterone levels after hCG stimulation or at pubertal age suggest that NR5A1 action may be less implicated in pubertal steroidogenesis than during fetal life.…”

“…More than 80 different NR5A1 variants, distributed across the full length of the protein, have been described and the majority are nonsynonymous mutations (Pedace et al, 2014; Tantawy et al, 2014; Woo et al, 2015; Fabbri et al, 2016). Most of these mutations are located in the DBD and are in a heterozygous state or compound heterozygous state with the p.Gly146Ala (rs1110061) variant, with the exception of two mild mutations described in homozygous state (Achermann et al, 2002; Soardi et al, 2010).…”

“…The reviewed data of seventy‐two 46,XY DSD patients with NR5A1 mutations reported in the literature, for whom information on presence or absence of Müllerian derivatives was available, suggested that Müllerian derivatives are present in about 24% of the cases (Pedace et al, 2014; Tantawy et al, 2014; Woo et al, 2015; Fabbri et al, 2016). However, persistently elevated FSH levels after puberty found in all patients studied suggest an impairment of Sertoli cells function in post pubertal age (Pedace et al, 2014).…”

“…Subsequently, it was shown that NR5A1 mutations are also a genetic cause of POI, with phenotypes ranging from primary to secondary amenorrhea, associated with infertility, hypoestrogenism, and elevated gonadotropin levels (Lourenço et al, 2009; Camats et al, 2012) Sisters and mothers of 46,XY DSD patients carrying heterozygous NR5A1 mutations may also develop premature ovarian failure (Lourenço et al, 2009; Camats et al, 2012; Fabbri et al, 2016). …”

“…In South America, familial and sporadic DSD patients bearing NR5A1 defects have been described in Brazil and Argentina (Lourenço et al, 2009; Ciaccio et al, 2012; Gabriel Ribeiro de Andrade et al, 2014; Fabbri et al, 2016). Here, we review the phenotype associated with ten novel and one previously described NR5A1 allelic variants identified in a Brazilian cohort of 46,XY and 46,XX DSD patients followed at a single tertiary center.…”