Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI)

Janse, Femi; Duran, Karen; Kloosterman, Wigard P.; Goverde, Angelique J.; Lambalk, Cornelis B.; Laven, Joop; Fauser, Bart C.J.M.; Giltay, Jacques C.

doi:10.1016/j.fertnstert.2011.10.032

Cited by 41 publications

(30 citation statements)

References 40 publications

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“…Mutations can be found in about 1.4-1.6% of women presenting with sporadic POI of unknown origin [16][17][18]21], with alterations of SF-1 including the hinge region, similarly to our patient.…”

Section: Discussionsupporting

confidence: 81%

“…In human women (46, XX), mutations in SF-1/NR5A1 seem to be associated with impairment of ovarian development and function leading to primary ovarian insufficiency due to low ovarian reserve. Indeed, SF-1 mutation has been reported in familial and sporadic cases of primary ovarian insufficiency (POI), albeit it is a rather rare cause in sporadic cases (1.4-8%) [16][17][18]. However, SF-1 alterations seem to lead to different degrees of severity of impairment of ovarian function, depending on the mutation.…”

Section: Introductionmentioning

confidence: 99%

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Clinical follow-up of the first SF-1 insufficient female patient

Gerster

Biason‐Lauber

Schoenle

2017

Annales d'Endocrinologie

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Objective. -Steroidogenic factor 1 (SF-1/NR5A1) plays a crucial role in regulating adrenal development, gonad determination and differentiation, and in the hypothalamic-pituitary control of reproduction and metabolism. In men (46, XY), it is known that mutations in SF-1/NR5A1 gene cause a wide phenotypic spectrum with variable degrees of undervirilization. In recent years, the role of SF-1 in the ovarian function was increasingly discussed and alterations in the gene were related to primary ovarian insufficiency. We describe the follow-up of a 46, XX affected woman with a SF-1 mutation and by comparing our case with the known manifestations reported in the literature, we try to further elucidate the function of SF-1 in the ovary. Results. -During infancy, adrenal insufficiency was the only clinical sign of the loss-of-function as ovarian development and function seemed normal. To date, this young woman aged 16.5 years shows normal growth, normal BMI and psychomotor development, has a normal puberty and regular menstruation. Conclusion. -This report shows one, to date uniquely described, phenotypic variant of SF-1 mutation in a 46, XX affected person with adrenocortical insufficiency but no ovarian dysfunction nor disturbance of pubertal development. To follow the natural history of SF-1 mutation in a 46, XX individual will further shed light on its role in the ovarian function and thus will help to counsel affected patients in future.Keywords: Steroidogenic factor 1; Adrenal insufficiency; Primary ovarian insufficiency; Disorder of sexual development RésuméObjectif. -Le facteur 1 stéroïdogénique (SF-1/NR5A1) joue un rôle critique dans la régulation du développement des surrénales, la détermination et différentiation des gonades ainsi que dans le contrôle hypothalamo-pituitaire de la reproduction et du métabolisme. Chez les hommes (46, XY), il est connu que les mutations du gène SF-1 peuvent entraîner de multiples phénotypes avec différents degrés d'impubérisme. Durant les dernières années, l'influence de SF-1 sur la fonction ovarienne a été étudié et les altérations de ce gène ont été mises en relation avec l'insuffisance ovarienne primaire. Nous décrivons le suivi d'une femme 46, XX porteuse d'une mutation du gène SF-1 et nous comparons notre cas clinique avec ceux de la littérature afin d'éclaircir l'influence du gène SF-1 sur la fonction ovarienne. Résultats. -Durant l'enfance, une insuffisance des surrénales fut le seul signe clinique de cette mutation, le développement des ovaires ainsi que leurs fonctions semblèrent alors normales. Actuellement cette adolescente de 16 ans a une croissance, un indice de masse corporelle et un développement psychomoteur normal, une puberté normale ainsi que des menstruations régulières. Conclusion. -Cette étude décrit une variante phénotypique, d'une personne 46, XX, atteinte d'une affection de SF-1 avec insuffisance surrénale mais sans dysfonctionnement ovarien ni perturbation de la puberté. Cette observation nous offre une opportunité unique de suivre l'histoire na...

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Clinical follow-up of the first SF-1 insufficient female patient

Gerster

Biason‐Lauber

Schoenle

2017

Annales d'Endocrinologie

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“…Mutations in the NR5A1 gene (MIM 184757; encoding steroidogenic factor 1 [SF-1]) have been associated with a spectrum of phenotypes ranging from primary adrenal insufficiency (AI) and complete 46,XY gonadal dysgenesis (6,7), to 46,XX primary AI, 46,XY DSD (disorders of sex development) including hypospadias (8,9), bilateral anorchia (10,11), hypogonadotropic hypogonadism (12), and primary ovarian failure (13)(14)(15)(16). Furthermore, according to the pivotal role of NR5A1 in regulating sex determination and differentiation, testicular descent, and reproduction (6,17), mutations in this gene have been recently associated in preliminary studies with severe forms of male factor infertility (18)(19)(20), with a frequency ranging from 0.7% (19), to 2.2% (20), to 3.5% (18).…”

mentioning

confidence: 99%

Mutational screening of NR5A1 gene encoding steroidogenic factor 1 in cryptorchidism and male factor infertility and functional analysis of seven undescribed mutations

Ferlin

Rocca

Vinanzi

et al. 2015

Fertility and Sterility

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“…Since the report by Lourenço et al (2009), several studies have described screening for NR5A1 mutations in POF women (Camats et al, 2012;Janse et al, 2012;Jiao et al, 2013;Lakhal et al, 2012;Philibert et al, 2013;Suwanai et al, 2013;Voican et al, 2013).…”

Section: Nr5a1mentioning

confidence: 99%

Aetiological coding sequence variants in non-syndromic premature ovarian failure: From genetic linkage analysis to next generation sequencing

Laissue

2015

Molecular and Cellular Endocrinology

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Premature ovarian failure (POF) is a frequent pathology affecting 1-1.5% of women under 40 years old. Despite advances in diagnosing and treating human infertility, POF is still classified as being idiopathic in 50-80% of cases, strongly suggesting a genetic origin for the disease. Different types of autosomal and X-linked genetic anomalies can originate the phenotype in syndromic and non-syndromic POF cases. Particular interest has been focused on research into non-syndromic POF causative coding variants during the past two decades. This has been based on the assumption that amino acid substitutions might modify the intrinsic physicochemical properties of functional proteins, thereby inducing pathological phenotypes. In this case, a restricted number of mutations might originate the disease. However, like other complex pathologies, POF might result from synergistic/compensatory effects caused by several low-to-mildly drastic mutations which have frequently been classified as non-functional SNPs. Indeed, reproductive phenotypes can be considered as quantitative traits resulting from the subtle interaction of many genes. Although numerous sequencing projects have involved candidate genes, only a few coding mutations explaining a low percentage of cases have been described. Such apparent failure to identify aetiological coding sequence variations might have been due to the inherent molecular complexity of mammalian reproduction and to the difficulty of simultaneously analysing large genomic regions by Sanger sequencing. The purpose of this review is to present the molecular and cellular effects caused by non-synonymous mutations which have been formally associated, by functional tests, with the aetiology of hypergonadotropic non-syndromic POF. Considerations have also been included regarding the polygenic nature of reproduction and POF, as well as future approaches for identifying novel aetiological genes based on next generation sequencing (NGS).

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Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI)

Cited by 41 publications

References 40 publications

Clinical follow-up of the first SF-1 insufficient female patient

Clinical follow-up of the first SF-1 insufficient female patient

Mutational screening of NR5A1 gene encoding steroidogenic factor 1 in cryptorchidism and male factor infertility and functional analysis of seven undescribed mutations

Aetiological coding sequence variants in non-syndromic premature ovarian failure: From genetic linkage analysis to next generation sequencing

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