An Amino-Terminal DAX1 (<i>NROB1</i>) Missense Mutation Associated with Isolated Mineralocorticoid Deficiency

Stuart, A. A. Verrijn; Özışık, Gökhan; Vroede, Monique A. de; Giltay, Jacques C.; Sinke, Richard J.; Peterson, Theresa J.; Harris, Rebecca M.; Weiss, Jeffrey; Jameson, J. Larry

doi:10.1210/jc.2005-2429

Cited by 37 publications

(23 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As previously reported for another amino-terminal nonsense close mutation, Q37X, the W39X mutation was also associated with a mild phenotype (5,8). Thus, it has been reported that gonadotrope function is often preserved in patients with mutations resulting in a N-terminal truncated DAX1 protein (5,6,7,8) that may provide sufficient DAX1 activity for gonadotrope cell development and function. We must, however, specify that the W39X mutation can also be associated with partial or complete gonadotropin deficiency as in the proband's brother described here or in the patients reported by Guclu et al (11).…”

Section: Discussionsupporting

confidence: 57%

“…Missense mutations, reported in about 20% of cases, are associated with more variable reproductive phenotypes (4,6,10,12). The recurrent (5, 11) W39X mutation found in our patient and in his affected brother leads to an amino-truncated DAX1 protein generated from an alternative in-frame translation start site and retaining partial activity (8).…”

Section: Discussionmentioning

confidence: 65%

“…In rare cases, onset occurs in early adulthood (4,10,11), sometimes with prominent effects on mineralocorticoid function (6,8,9,10). The phenotypes of the proband, his brother, and his nephew illustrate the different possible adrenal consequences of identical DAX1 mutations (12,13).…”

Section: Discussionmentioning

confidence: 99%

“…Some reports have described partial pubertal development and oligospermia in rare patients with DAX1 mutations, in whom low serum testosterone concentrations indicated partial gonadotropic deficiency (4,10). More recently, men with missense mutations located in the amino-terminal portion of DAX1 (W105C and C200W) were reported to have an apparently normal hypothalamic-pituitary-gonadal axis with no signs or symptoms of hypogonadism (6,7). In these families, the disease was revealed by mild adrenal disorders in the affected probands, whereas male relatives carrying the same mutation seemed to have apparently normal pubertal development and sexual function (6, 7).…”

Section: Discussionmentioning

confidence: 99%

“…A few cases of partial HHG have also been described, with clear clinical and biological signs but no subjective symptoms (4,5). Rare cases of apparently preserved gonadotropin secretion have been reported but not fully documented in patients with DAX1 mutations (6,7).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic–pituitary–gonadal axis but deteriorating oligospermia during long-term follow-up

Raffin-Sanson

Oudet

Salenave

et al. 2013

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: DAX1/NR0B1 mutations cause primary adrenal insufficiency in early childhood and hypogonadotropic hypogonadism (HHG), leading to absent or incomplete sexual maturation. The aim of the study was to prospectively investigate gonadotrope and testicular functions in a patient carrying a DAX1 mutation, who had spontaneous puberty and normal virilization but oligospermia. Case report: The proband was referred for infertility at the age of 32 years. He reported adrenal insufficiency diagnosed at the age of 19 years. Puberty started at the age of 13 years, with spontaneous virilization, growth spurt, and testicular growth. He reported normal libido and sexual function. Physical examination showed normal virilization, penile length, and testicular volume. However, semen samples showed severe oligospermia. Hormonal measurements confirmed adrenal insufficiency but showed a preserved hypothalamic-pituitary-gonadal axis with normal testosterone and inhibin B; basal and GNRH-stimulated gonadotropin levels and LH pulsatility were also normal. He fathered a first boy by in vitro fertilization and a second boy without medical assistance. As a nephew also had early adrenal insufficiency, the possibility of DAX1 mutation was raised. The same recurrent hemizygous nonsense mutation W39X was found in the proband, his nephew, and in an apparently asymptomatic brother who was found to have adrenal insufficiency, mild HHG, and azoospermia. Several evaluations of the proband over 20 years showed preserved testosterone levels and LH secretion but deteriorating oligospermia. Conclusion: Long-term preservation of normal hypothalamic-pituitary-gonadal function in this patient, contrasting with his severe oligospermia, strongly suggests that DAX1 is required for human spermatogenesis, independently of its known role in gonadotropin secretion.

show abstract

Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic–pituitary–gonadal axis but deteriorating oligospermia during long-term follow-up

Raffin-Sanson

Oudet

Salenave

et al. 2013

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

New insights into X‐linked adrenal hypoplasia congenita from a novel splice‐site variant of NR0B1 and adrenal CT images

Jiang

Peng

Zhao

et al. 2023

Molec Gen & Gen Med

View full text Add to dashboard Cite

Background X‐linked adrenal hypoplasia congenita (AHC) is a rare disorder, often manifesting as primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), and caused by variants of NR0B1, most of which are frame‐shifting variants, and few splice‐site variants. Methods and Results Here, a novel splice‐site variant of NR0B1 (NM_000475.4), c.1169‐2A>T (patient 1), and a stop‐loss variant of NR0B1 c.1411T>C (patient 2) are described in this study. We perform minigene assays for the splice‐site variant (c.1169‐2A>T) and determine that the variant causes exon 2 skipping. Moreover, the defect of NR0B1 protein may bring about the severe phenotype of the patient. Through 8 years of follow‐up, we compare the CT images from 8 years ago with the latest image, and observe the CT image change of adrenal in patient 2 (from the increased thickness of adrenal to adrenal atrophy). Conclusion X‐linked adrenal hypoplasia congenita is produced by variants of NR0B1. We report a case that presents a novel splice‐site variant, which has been verified that it could lead to the exon 2 skipping in the RNA splicing progress. Moreover, we report the adrenal CT image change of patient 2, which has never been referred to before, and expand the spectrum of X‐linked AHC characteristics.

show abstract

Dax-1 Knockdown in Mouse Embryonic Stem Cells Induces Loss of Pluripotency and Multilineage Differentiation

et al. 2009

View full text Add to dashboard Cite

Dax-1 (Nr0b1) is an orphan member of the nuclear hormone receptor superfamily that has a key role in adrenogonadal development and function. Recent studies have also implicated Dax-1 in the transcriptional network controlling embryonic stem (ES) cell pluripotency. Here, we show that Dax-1 expression is affected by differentiating treatments and pharmacological activation of b-catenin-dependent transcription in mouse ES cells. Furthermore, Dax-1 knockdown induced upregulation of multilineage differentiation markers, and produced enhanced differentiation and defects in ES viability and proliferation. Through RNA interference and transcriptome analysis, we have identified genes regulated by Dax-1 in mouse ES cells at 24 and 48 hours after knockdown. Strikingly, the great majority of these genes are upregulated, showing that the prevalent function of Dax-1 is to act as a transcriptional repressor in mouse ES cells, as confirmed by experiments using the Gal4 system. Genes involved in tissue differentiation and control of proliferation are significantly enriched among Dax-1-regulated transcripts. These data show that Dax-1 is an essential element in the molecular circuit involved in the maintenance of ES cell pluripotency and have implications for the understanding of stem cell function in both physiological (adrenal gland) and clinical (Ewing tumors) settings where Dax-1 plays a pivotal role in development and pathogenesis, respectively.

show abstract

An Amino-Terminal DAX1 (NROB1) Missense Mutation Associated with Isolated Mineralocorticoid Deficiency

Abstract: We describe the first missense mutation in the aminoterminus of DAX1 and conclude that mutations in this region may be partially compensated by redundant functional domains. Mild DAX1 mutations may be a cause of isolated mineralocorticoid deficiency.

Cited by 37 publications

References 24 publications

A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic–pituitary–gonadal axis but deteriorating oligospermia during long-term follow-up

A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic–pituitary–gonadal axis but deteriorating oligospermia during long-term follow-up

New insights into X‐linked adrenal hypoplasia congenita from a novel splice‐site variant of NR0B1 and adrenal CT images

Dax-1 Knockdown in Mouse Embryonic Stem Cells Induces Loss of Pluripotency and Multilineage Differentiation

Contact Info

Product

Resources

About