Mutation update for theNR5A1gene involved in DSD and infertility

Fabbri‐Scallet, Helena; Sousa, Lizandra Maia de; Maciel‐Guerra, Andréa T.; Guerra‐Júnior, Gil; Mello, Maricilda Palandi de

doi:10.1002/humu.23916

Cited by 64 publications

(75 citation statements)

References 102 publications

(77 reference statements)

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“…However, the precise mechanism by which NR5A1 action fails and leads to DSD is not fully understood, nor has an explanation been provided for the wide-ranging phenotypes associated with different and, in some cases identical, NR5A1 variants. This is despite numerous studies attempting to resolve this question by analyzing defective NR5A1 function at steroidogenic target promoter (such as CYP11A1, CYP17A1, and CYP19A1) or sex differentiation genes (AMH and INSL3) [57].…”

Section: Nr5a1 (Sf1) and Wt1: Old Genes New Mechanismsmentioning

confidence: 99%

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

Gomes

Chetty

Jørgensen

et al. 2020

IJMS

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Disorders (or differences) of sex development (DSD) are a heterogeneous group of congenital conditions with variations in chromosomal, gonadal, or anatomical sex. Impaired gonadal development is central to the pathogenesis of the majority of DSDs and therefore a clear understanding of gonadal development is essential to comprehend the impacts of these disorders on the individual, including impacts on future fertility. Gonadal development was traditionally considered to involve a primary ‘male’ pathway leading to testicular development as a result of expression of a small number of key testis-determining genes. However, it is increasingly recognized that there are several gene networks involved in the development of the bipotential gonad towards either a testicular or ovarian fate. This includes genes that act antagonistically to regulate gonadal development. This review will highlight some of the novel regulators of gonadal development and how the identification of these has enhanced understanding of gonadal development and the pathogenesis of DSD. We will also describe the impact of DSDs on fertility and options for fertility preservation in this context.

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Section: Nr5a1 (Sf1) and Wt1: Old Genes New Mechanismsmentioning

confidence: 99%

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

Gomes

Chetty

Jørgensen

et al. 2020

IJMS

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“…Thus, our study, similar to others [41][42][43][44], was not able to demonstrate a disease-causing effect leaving genotype-phenotype correlation for NR5A1 variants unsolved. Many patients with variants in NR5A1 have been described with broad phenotypes ranging from severe 46,XY DSD to unvirilized males with/without adrenal failure, 46,XX with ovarian insufficiency, 46,XX with ovotesticular DSD, and healthy carriers [45]. On the other hand, it has also been shown that SF-1 has an extraordinary network of regulators, modulators, and target genes [46][47][48].…”

Section: Hts In a Second Approach To Detect Digenic Or Oligogenic Orimentioning

confidence: 99%

“…We therefore performed a WES analysis in four of these 46,XY DSD patients with heterozygous NR5A1 gene defects [13] in search for additional genetic hits explaining the phenotypic variability described in patients with NR5A1 mutations [45]. For specific bioinformatic analysis, candidate genes for DSD and genes related to NR5A1 were collected from the literature and databases including known and potential candidate genes.…”

Section: Hts In a Second Approach To Detect Digenic Or Oligogenic Orimentioning

confidence: 99%

Oligogenic Origin of Differences of Sex Development in Humans

Camats

Flück

Audí

2020

IJMS

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Sex development is a very complex biological event that requires the concerted collaboration of a large network of genes in a spatial and temporal correct fashion. In the past, much has been learned about human sex development from monogenic disorders/differences of sex development (DSD), but the broad spectrum of phenotypes in numerous DSD individuals remains a conundrum. Currently, the genetic cause of less than 50% of DSD individuals has been solved and oligogenic disease has been proposed. In recent years, multiple genetic hits have been found in individuals with DSD thanks to high throughput sequencing. Our group has been searching for additional genetic hits explaining the phenotypic variability over the past years in two cohorts of patients: 46,XY DSD patients carriers of NR5A1 variants and 46,XY DSD and 46,XX DSD with MAMLD1 variants. In both cohorts, our results suggest that the broad phenotypes may be explained by oligogenic origin, in which multiple hits may contribute to a DSD phenotype, unique to each individual. A search for an underlying network of the identified genes also revealed that a considerable number of these genes showed interactions, suggesting that genetic variations in these genes may affect sex development in concert.

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“…Loss of functions mutations of NR5A1 lead to complete adrenal and gonadal agenesis, alterations in virilization, and retention of Müllerian ducts in XY mice [Sadovsky et al, 1995]. In humans, NR5A1 gene variants are responsible for a wide spectrum of phenotypes, including adrenal insufficiency, disorder of sex development (DSD), and primary ovarian insufficiency [Achermann et al, 1999[Achermann et al, , 2002Lourenço et al, 2009;Suntharalingham et al ., 2015;Robevska et al, 2018;Fabbri-Scallet et al, 2020]. In addition, mutations in the NR5A1 gene have been found in males with bilateral anorchia, isolated hypospadias, male infertility, and in some subjects with adrenal tumors and endometriosis [reviewed in Ferraz-de-Souza et al, 2011;Fabbri-Scallet et al, 2020].…”

mentioning

confidence: 99%

“…In humans, NR5A1 gene variants are responsible for a wide spectrum of phenotypes, including adrenal insufficiency, disorder of sex development (DSD), and primary ovarian insufficiency [Achermann et al, 1999[Achermann et al, , 2002Lourenço et al, 2009;Suntharalingham et al ., 2015;Robevska et al, 2018;Fabbri-Scallet et al, 2020]. In addition, mutations in the NR5A1 gene have been found in males with bilateral anorchia, isolated hypospadias, male infertility, and in some subjects with adrenal tumors and endometriosis [reviewed in Ferraz-de-Souza et al, 2011;Fabbri-Scallet et al, 2020]. So far, a clear genotypephenotype correlation has not been established yet, and a polygenic inheritance might explain the broad phenotypic variability associated with NR5A1 gene mutations [Ma-zen et al, 2016;Camats et al, 2018].…”

mentioning

confidence: 99%

NR5A1 Gene Variants: Variable Phenotypes, New Variants, Different Outcomes

Faienza

Chiarito

Baldinotti³

et al. 2019

Sex Dev

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NR5A1 (nuclear receptor subfamily 5 group A member 1) is a transcriptional regulator of adrenal and gonadal development and function. Heterozygous and homozygous NR5A1 mutations have been described in people with 46,XY disorders of sex development (DSD). The clinical, endocrine, and genetic features of four 46,XY subjects with NR5A1 genetic variants (2 sisters, 2 boys) from 3 unrelated families are reported. All subjects presented with hypergonadotropic hypogonadism and abnormal pubertal progression. Markers of Sertoli cell function were more affected than those of Leydig cell function. Genetic investigation demonstrated the presence of different heterozygous NR5A1 genetic variants. In the boys, pathogenetic NR5A1 gene variants were found that had been previously reported. The 2 sisters carried a new genetic variant in exon 4, and in silico analysis and ACMG classification indicated its pathogenicity. The data confirmed that NR5A1 gene mutations may present with variable genital phenotypes. Anyway, reproductive function was always impaired. Any clinical or endocrine data seem to be unable to differentiate these patients from other 46,XY DSD cases, suggesting that molecular analysis must be warranted. In subjects with NR5A1 mutations, different decisions in sex assignment may permit satisfying somatic and psychological outcome, but any option requires hormonal substitutive therapy from adolescence onward.

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Mutation update for theNR5A1gene involved in DSD and infertility

Cited by 64 publications

References 102 publications

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

Oligogenic Origin of Differences of Sex Development in Humans

NR5A1 Gene Variants: Variable Phenotypes, New Variants, Different Outcomes

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