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

Steroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309-320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

Domenice S ，Machado AZ ，Ferreira FM ，Ferraz-de-Souza B ，Lerario AM ，Lin L ，Nishi MY ，Gomes NL ，da Silva TE ，Silva RB ，Correa RV ，Montenegro LR ，Narciso A ，Costa EM ，Achermann JC ，Mendonca BB ... -  《-》

Update--steroidogenic factor 1 (SF-1, NR5A1).

Köhler B ，Achermann JC 《Minerva Endocrinologica》

Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals.

Camats N ，Pandey AV ，Fernández-Cancio M ，Andaluz P ，Janner M ，Torán N ，Moreno F ，Bereket A ，Akcay T ，García-García E ，Muñoz MT ，Gracia R ，Nistal M ，Castaño L ，Mullis PE ，Carrascosa A ，Audí L ，Flück CE ... -  《-》

The novel p.Cys65Tyr mutation in NR5A1 gene in three 46,XY siblings with normal testosterone levels and their mother with primary ovarian insufficiency.

Fabbri HC ，de Andrade JG ，Soardi FC ，de Calais FL ，Petroli RJ ，Maciel-Guerra AT ，Guerra-Júnior G ，de Mello MP ... -  《BMC Medical Genetics》

A report of two novel NR5A1 mutation families: possible clinical phenotype of psychiatric symptoms of anxiety and/or depression.

NR5A1 or steroidogenic factor 1 is a nuclear receptor that plays important roles in the hypothalamus-pituitary-steroidogenic axis. The clinical phenotype of most 46,XY mutation carriers includes disorders of sex development (DSD) without adrenal insufficiency, whereas 46,XX mutation carriers have phenotypes ranging from no symptoms to ovarian insufficiency. Although genetically engineered ventromedial hypothalamus-specific Nr5a1 knockout mice show anxiety behaviour, no psychiatric symptoms have been reported in human NR5A1 mutation carriers. We report clinical and molecular findings for individuals (from two families) with NR5A1 mutations, showing psychiatric symptoms. We screened for NR5A1 mutations in a cohort of 34 patients with 46,XY DSD using PCR-based sequencing. Psychiatric symptoms were assessed using mental health assessment tools and structured clinical interviews. Functional properties of detected mutant NR5A1s were studied in silico and in vitro, including three-dimensional (3D) mutation models, subcellular NR5A1 protein localization and transactivation assays. We found 2 (46,XY) patients with NR5A1 heterozygous novel mutations (p.D257fs and p.V424del), which were transmitted from their respective mothers. The patients' clinical findings indicated DSD without adrenal insufficiency. Both mothers showed psychiatric symptoms, including excessive anxiety and/or depression. The mother and grandmother of one patient had premature ovarian insufficiency. Functional studies showed altered 3D models of p.V424del and normal subcellular NR5A1 localization and impaired transcriptional activation without dominant-negative effects in both mutations. We found 2 (46,XX) NR5A1 mutation carriers with excessive anxiety and/or depression. These results suggest that excessive anxiety and/or depression are possible clinical phenotypes of 46,XX NR5A1 mutations.

Suwanai AS ，Ishii T ，Haruna H ，Yamataka A ，Narumi S ，Fukuzawa R ，Ogata T ，Hasegawa T ... -  《-》