Testicular Dysgenesis without Adrenal Insufficiency in a 46,XY Patient with a Heterozygous Inactive Mutation of Steroidogenic Factor-1 (original) (raw)
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The Journal of Clinical Endocrinology & Metabolism, 2007
Context-Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis, and reproduction. Targeted deletion of Nr5a1 (Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Müllerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus) and primary adrenal failure.
Human Mutation, 2008
Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in two 46,XY female patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 27 patients with 46,XY disorders of sex development (DSD) from the German network of DSD. Heterozygous SF1 mutations were found in 5 out of 27 (18.5%) of cases. Four patients with SF1 mutations presented with the similar phenotype of mild gonadal dysgenesis, severe underandrogenization, and absent Müllerian structures. Of these, two patients harbored missense mutations within the DNA-binding region of SF1 (p.C33S, p.R84H), one patient had a nonsense mutation (p.Y138X) and one patient had a frameshift mutation (c.1277dupT) predicted to disrupt RNA stability or protein function. One additional patient ([c.424_427dupCCCA]1[p.G146A]) displayed a more marked phenotype of severe gonadal dysgenesis, normal female external genitalia, and Müllerian structures. Functional studies of the missense mutants (p.C33S, p.R84H) and of one nonsense mutant (p.Y138X) revealed impaired transcriptional activation of SF1-responsive target genes. To date, adrenal insufficiency has not occurred in any of the patients. Thus, SF1 mutations are a relatively frequent cause of 46,XY DSD in humans. Hum Mutat 29(1), 59-64, 2008. r r 2007 Wiley-Liss, Inc.
The Journal of Clinical Endocrinology & Metabolism, 2007
Context: The clinical and biological features of Sertoli cell and Leydig cell dysfunction are usually investigated when characterizing disorders of sex development in 46,XY individuals: This allows gonadal dysgenesis, a defective development of the gonad, to be distinguished from defects restricted to androgen synthesis or sensitivity. In humans, mutations in steroidogenic factor-1 (SF-1), one of the critical factors involved in testis development, have been reported to cause gonadal dysgenesis with or without adrenal failure in 46,XY individuals. Objective: We report a SF-1 mutation that caused ambiguous genitalia associated with strikingly different hormonal phenotypes in two affected 46,XY children from the same family. Methods: Hormonal evaluation included testosterone (T), anti-Mullerian hormone (AMH), inhibin B, FSH, and LH measurements during the first weeks of life, a period when physiological activation of the gonadotropin-gonadal system occurs. Direct DNA sequencing of the coding sequence of the SF-1 and the androgen receptor (AR) genes was performed. Results: Both 46,XY children had ambiguous genitalia with no Mullerian structures and no adrenal insufficiency. The older child showed normal elevation of T (up to 7.6 nmol/liter, 2.2 ng/ml), AMH (504 pmol/liter, 70.6 ng/ml), inhibin B (245 pg/ml), FSH, and LH during the first weeks, which led to a presumptive diagnosis of partial androgen insensitivity syndrome. The AR sequence was, however, normal. In the second child, T, AMH, and inhibin B were low, suggesting gonadal dysgenesis. In both children and their mother, a c.536delC frameshift mutation in the SF-1 gene was found. This mutation terminates translation at position 295, removing the ligand-binding domain and the activation function 2 (AF-2) domain, a critical domain for SF-1 transactivating activity. Conclusions: The usual markers of testis dysgenesis may be normal in 46,XY individuals with SF-1 mutation. Screening for SF-1 mutation should be performed in subjects with apparent partial androgen insensitivity syndrome and no mutation in the AR gene.
Andrologia, 2016
Steroidogenic factor-1 (SF-1), also known as nuclear receptor subfamily 5 group A member 1 (NR5A1), is a member of orphan receptor subfamily and located on chromosome 9 (9q33). In 46, XY individuals with mutation of SF-1 gene, adrenal failure, testis dysgenesis, androgen synthesis defects, hypospadias and anorchia with microphallus, infertility can occur from severe to mild. We report a case of a 20-day-old male who is admitted to our clinic due to ambiguous genitalia. In this report, we describe a novel heterozygous c.814A > C (p. T272P) NR5A1 mutation in a patient with 46, XY DSD without adrenal insufficiency. We describe a novel missense mutation c.814A > C (p. T272P) in NR5A1 gene which had not previously been reported. Also this report highlights that the potential diagnostic utility of next-generation sequencing is an effective strategy versus Sanger sequencing to identify genetic mosaicism in clinical practice.
Journal of Pediatric and Adolescent Gynecology, 2014
Background: Steroidogenic factor-1 (SF-1) gene (NR5A1) mutations cause disorders of sexual development due to gonadal dysgenesis, particularly in 46,XY individuals. In cases exhibiting this mutation, the phenotype is heterogeneous, and it may vary within a spectrum ranging from complete female appearance to an infertile male. Virilization observed in some cases in the pubertal age group may lead to diagnostic difficulties. Case: The present case report describes the clinical, histopathologic, and genetic characteristics of a 46,XY case, who was born with a female phenotype and raised as a girl, presented with findings of virilization in the pubertal period. She had no germ cells and very few Leydig cells with atrophic testis on biopsy and in whom a novel heterozygous mutation in the SF-1 gene (a heterozygous 7-bp deletion mutation in exon 7 [c.1308-1314del7bp] causing frameshift) was identified. Summary and Conclusion: Although the gonads are very dysgentic in patient with SF-1 mutations, sufficient androgen synthesis can cause severe virilization during puberty.
European Journal of Endocrinology, 2014
Objective: Steroidogenic factor 1 (SF-1, NR5A1) is a key transcriptional regulator of genes 33 involved in the hypothalamic-pituitary-gonadal axis. Recently, SF-1 mutations were found to 34 be a frequent cause of 46,XY DSD in humans. We investigate the frequency of NR5A1 35 mutations in an Egyptian cohort of XY,DSD. 36 37 Design: Clinical assessment, endocrine evaluation and genetic analysis of 50 Egyptian 38 XY,DSD patients (without adrenal insufficiency) with a wide phenotypic spectrum. 39 40 Methods: Molecular analysis of NR5A1 gene by direct sequencing followed by in vitro 41 functional analysis of the two novel missense mutations detected. 42 43 Results: Three novel heterozygous mutations of the coding region in patients with 44 hypospadias were detected. p.Glu121AlafsX25 results in severely truncated protein, 45 p.Arg62Cys lies in DNA-binding zinc finger whereas p.Ala154Thr lies in the hinge region of 46 SF-1 protein. Transactivation assays using reporter constructs carrying promoters of AMH, 47 CYP11A1 and Tesco core enhancer of Sox9 showed that p.Ala154Thr and p.Arg62Cys 48 mutations result in aberrant biological activity of NR5A1. Seventeen patients (34%) harboured 49 the p.Gly146Ala polymorphism. 50 51 Conclusion: We identified two novel NR5A1 mutations showing impaired function in 23 52
The Journal of Clinical Endocrinology & Metabolism, 2004
Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that plays key roles in endocrine development and function. Knockout mice lacking SF-1 have adrenal and gonadal agenesis, impaired gonadotropin expression, and structural abnormalities of the ventromedial hypothalamic nucleus. Previous studies have identified three human subjects with mutations in SF-1 causing adrenocortical insufficiency with varying degrees of gonadal dysfunction. We now describe a novel 8-bp microdeletion of SF-1, isolated from a 46, XY patient who presented with gonadal agenesis but normal adrenal function, which causes premature termination upstream of sequences encoding the activation function 2 domain. In cell transfection experiments, the mutated protein possessed no intrinsic transcriptional activity but rather inhibited the function of the wild-type protein in most cell types. To our knowledge, this is the first example of an apparent dominantnegative effect of a SF-1 mutation in humans. These findings, which define a SF-1 mutation that apparently differentially affects its transcriptional activity in vivo in the adrenal cortex and the gonads, may be relevant to the cohort of patients who present with 46, XY sex reversal but normal adrenal function.
Multifunctional role of steroidogenic factor 1 and disorders of sex development
Arquivos Brasileiros de Endocrinologia & Metabologia, 2011
Disorders of sex development (DSD) involve several conditions that result from abnormalities during gonadal determination and differentiation. Some of these disorders may manifest at birth by ambiguous genitalia; others are diagnosed only at puberty, by the delayed onset of secondary sexual characteristics. Sex determination and differentiation in humans are processes that involve the interaction of several genes such as WT1, NR5A1, NR0B1, SOX9, among others, in the testicular pathway, and WNT4, DAX1, FOXL2 and RSPO1, in the ovarian pathway. One of the major proteins in mammalian gonadal differentiation is the steroidogenic nuclear receptor factor 1 (SF1). This review will cover some of the most recent data on SF1 functional roles and findings related to mutations in its coding gene, NR5A1. Arq Bras Endocrinol Metab. 2011;55(8):607-12
Journal of Clinical Investigation, 1975
A B S T R A C T A partial testicular defect in testosterone secretion has been documented in a pubertal male with a congenital adrenal hyperplasia due to hereditary deficiency of the A5-isomerase-3fi-hydroxysteroid dehydrogenase enzyme complex (AY-3j-HSD). Diagnosis of the enzymatic defect is based on the clinical picture of ambiguous genitalia and salt-losing crisis in infancy, together with high urinary A5-pregnenetriol and plasma dehydroepiandrosterone when the patient was taken off replacement corticoid treatment. No hormonal response to ACTH or salt deprivation was demonstrable. In addition, in vivo studies revealed a partial enzymatic defect in the testis. Although plasma testosterone was low-normal (250 ng/100 ml), plasma A5-androstenediol was markedly elevated and rose to a greater extent than testosterone after human chorionic gonadotropin administration. In vitro testicular incubation studies suggested a testicular A5-3%-HSD enzyme defect with less A4 products formed from A5 precursors than in a control testis. Histochemical studies of the testis were also consistent with this defect. Testicular biopsy revealed spermato-An abstract of a portion of this work has appeared in Pediatr. Res. genic arrest, generally diminished Leydig cells, but with focal areas of Leydig cell hyperplasia as well as benign Leydig cell nodules within the spermatic cord. In vivo studies of steroid metabolism suggested intact peripheral or hepatic A5-3i#-HSD activity. These studies imply that A5-3p-HSD activity differs in the gonad, adrenal, and peripheral organs. These findings are compatible with the concept that the enzyme complex consists of subunits and/or that enzymes in these organs are under different genetic control.