X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein

Lehmann, Sylvia; Lalli, Enzo; Sassone–Corsi, Paolo

doi:10.1073/pnas.122044099

Cited by 45 publications

(41 citation statements)

References 51 publications

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“…Furthermore, the p.Cys66GlyfsX2 mutant of DAX1 predominantly located in the cytoplasm. It has been shown that LXXLL motifs and an intact structure of the LBD are crucial for the nuclear localization of DAX1 (34,35). However, the truncated p.Cys66GlyfsX2 mutant of DAX1 only retained the first LXXLL motif, which may have resulted in the abnormal intracellular distribution of the mutant DAX1.…”

Section: Discussionmentioning

confidence: 99%

X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism: Identification and in vitro study of a novel small indel in the NR0B1 gene

Yu¹,

Wang²,

Yu³

et al. 2016

Molecular Medicine Reports

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Abstract. DAX1 is an orphan nuclear receptor that has a key role in the development and function of the adrenal and reproductive axes. Mutations in NR0B1, the gene encoding DAX1, result in X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). A Chinese pedigree with X-linked AHC and HHG was investigated in the present study. Sequence analysis identified a novel small indel variant, c.195_207delinsTG, in the NR0B1 gene. To determine the effect of this variant on DAX1 expression, reverse-transcription quantitative PCR and western blot assays were performed. The mRNA expression levels in carriers of mutant NR0B1 were significantly reduced (62% decrease) compared to those in individuals with wild-type NR0B1 (WT). The c.195_207delinsTG mutation was demonstrated to lead to various truncated DAX1 proteins, including the C-terminal truncated DAX1, which was only detected in the cytoplasm, and the N-terminal truncated DAX1, which was present in the cytoplasm and nucleus. A luciferase assay was then performed to assess the repressor function of DAX1 in modulating steroidogenic factor 1 (SF-1)-mediated transactivation. WT DAX1 significantly suppressed the SF-1-mediated promoter activity of the steroidogenic acute regulatory protein by 35.5±1.9%. In contrast to other known pathogenic mutations which abolish the repressor function of DAX1, the c.195_207delinsTG mutant proxkduced a higher repressor activity, demonstrating a 49.9±2.6% reduction of promoter activity. These findings suggested that the mutation of NR0B1 in X-linked AHC with HHG enhanced the function of DAX1 to repress SF-1 activation, while DAX1 is expected to have additional roles in the pathological mechanism. Introduction X-linked adrenal hypoplasia congenita (AHC) is a rare genetic disorder of adrenal gland development, characterized by absence or near absence of the permanent zone of the adrenal cortex (1). Patients with this condition usually present with primary adrenal failure, including salt-wasting, hyperpigmentation, failure to thrive, reduced serum cortisol and aldosterone and increased plasma adrenocorticotropic hormone (ACTH) (2). The majority of patients present with symptoms within the first two months of their life, whereas the remainder present later in childhood (3,4). The condition is lethal if left untreated with appropriate steroid hormones (5). Besides adrenal insufficiency, hypogonadotropic hypogonadism (HHG) is a frequent feature of X-linked AHC. It is usually recognized during adolescence by the absence or interruption of normal pubertal development (6,7).X-linked AHC was originally mapped to Xp21 and the nuclear receptor sub-family 0, group B, member 1 (NR0B1) was subsequently identified by positional cloning as the gene responsible for X-linked AHC and HHG (2,(8)(9)(10)(11). The NR0B1 gene consists of two exons and encodes a 470-amino acid protein termed dosage-sensitive sex-reversal, adrenal hypoplasia congenital critical region on the X chromosome, protein 1 (DAX1) (12). DAX1 is an orphan member of the ...

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Section: Discussionmentioning

confidence: 99%

X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism: Identification and in vitro study of a novel small indel in the NR0B1 gene

Yu¹,

Wang²,

Yu³

et al. 2016

Molecular Medicine Reports

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“…S5C). (46,47). With the exception of these two regions, the rest of the Dax-1 LBD folds into a well-defined, compact structure.…”

Section: Preparation and Characterization Of The (Dax-1)2:lrh-1 Hetermentioning

confidence: 99%

The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1

Sablin¹,

Woods²,

Krylova

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The Dax-1 protein is an enigmatic nuclear receptor that lacks an expected DNA binding domain, yet functions as a potent corepressor of nuclear receptors. Here we report the structure of Dax-1 bound to one of its targets, liver receptor homolog 1 (LRH-1). Unexpectedly, Dax-1 binds to LRH-1 using a new module, a repressor helix built from a family conserved sequence motif, PCFXXLP. Mutations in this repressor helix that are linked with human endocrine disorders dissociate the complex and attenuate Dax-1 function. The structure of the Dax-1:LRH-1 complex provides the molecular mechanism for the function of Dax-1 as a potent transcriptional repressor.Dax-1 ͉ LRH-1 ͉ nuclear receptor ͉ regulation ͉ structure T he orphan nuclear receptor DAX-1/Dax-1 (dosage-sensitive sex-reversal adrenal hypoplasia congenital critical region on the X chromosome gene 1) (1) is well known for its role in human pathophysiology. Duplication of the DAX-1 gene causes phenotypic sex reversal in XY individuals (2), and mutations in DAX-1 are responsible for adrenal hypoplasia congenita, an inherited disorder of adrenal gland development (3). During embryogenesis, Dax-1 functions to direct cell differentiation in testes and adrenal tissues (1). In adult physiology, Dax-1 acts as a global repressor of many nuclear receptors, including SF-1, Nur77, ERR␥, ER, AR, PR, and LRH-1 (4-13). Dax-1 also is indispensable to maintaining the pluripotent state of embryonic stem cells (14,15).There is a little information on either the structure or regulatory mechanisms of Dax-1. Dax-1 belongs to a unique family of nuclear receptors (NR0B1) that lack the essential DNA binding domain. Instead, the human Dax-1 N terminus consists of three sequence repeats that include the LXXL/ML motif (''LXXL/ML boxes'' 1-3) (16). This unique N-terminal extension is thought to play a role in subcellular distribution and nuclear localization of . No homologues for the N-terminal region of Dax-1 are known, but its C-terminal domain is a clear homologue of the nuclear receptor ligandbinding domain (LBD) (1). To date, no hormone for Dax-1 has been identified, and the mechanism of its function as corepressor remains under debate (4, 5, 7-9, 12, 18-20). The elucidation of Dax-1 mechanisms has been frustrated by a lack of highresolution structural information. Here we report the first structure of Dax-1 bound to its physiological target, nuclear receptor liver receptor homolog 1 (LRH-1; NR5A2).LRH-1 was first discovered in the liver and intestine, where it regulates genes controlling bile acid synthesis and cholesterol homeostasis (21-24). Recently, LRH-1 was found in human steroidogenic tissues and was shown to activate transcription of genes encoding steroidogenic enzymes (25). In particular, regulation of the CYP19A gene encoding aromatase, which converts androgens to estrogens, gives LRH-1 a pivotal role in estrogen signaling (25-28). Similar to Dax-1, LRH-1 is indispensable to maintaining the pluripotent state of embryonic stem cells (29).Unlike other nuclear receptors that func...

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“…Among corepressors, DAX-1 was shown to interact with N-CoR [63] and Alien [64], even if further studies have ruled out a role of N-CoR as a bona fide DAX-1 corepressor [65]. However, site-directed mutagenesis of conserved surface residues in DAX-1, which in other nuclear receptors are involved in corepressor interaction, does not impair DAX-1 transcriptional silencing properties (see Section 6) [66].…”

Section: Advances In Biologymentioning

confidence: 99%

“…Third, the Dax-1 mutant ΔV271, which corresponds to the human AHC mutant ΔV269, behaves similarly to the wild type. However, the localization of this mutant is shifted to the cytoplasm (see below Section 6) [65,66] and it is difficult to explain how it may regulate promoter expression in the nucleus. Further studies are then needed to assess the role of potential interactions between DAX-1 and RNA transcriptional cofactors in the regulation of gene expression.…”

Section: Advances In Biologymentioning

confidence: 99%

Role of Orphan Nuclear Receptor DAX-1/NR0B1 in Development, Physiology, and Disease

Lalli

2014

Advances in Biology

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is an unusual orphan receptor that has a pivotal role in the development and function of steroidogenic tissues and of the reproductive axis. Recent studies have also indicated that this transcription factor has an important function in stem cell biology and in several types of cancer. Here I critically review the most important findings on the role of DAX-1 in development, physiology, and disease of endocrine tissues since the cloning of its gene twenty years ago.

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X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein

Cited by 45 publications

References 51 publications

X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism: Identification and in vitro study of a novel small indel in the NR0B1 gene

X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism: Identification and in vitro study of a novel small indel in the NR0B1 gene

The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1

Role of Orphan Nuclear Receptor DAX-1/NR0B1 in Development, Physiology, and Disease

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