Article

Hypogonadotropic hypogonadism in subjects with DAX1 mutations

Division of Endocrinology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Molecular and Cellular Endocrinology (Impact Factor: 4.24). 06/2011; 346(1-2):65-73. DOI: 10.1016/j.mce.2011.04.017
Source: PubMed

ABSTRACT DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1; also known as NROB1, nuclear receptor subfamily 0, group B, member 1) encodes a nuclear receptor that is expressed in embryonic stem (ES) cells, steroidogenic tissues (gonads, adrenals), the ventromedial hypothalamus (VMH), and pituitary gonadotropes. Humans with DAX1 mutations develop an X-linked syndrome referred to as adrenal hypoplasia congenita (AHC). These boys typically present in infancy with adrenal failure but later fail to undergo puberty because of hypogonadotropic hypogonadism (HHG). The adrenal failure reflects a developmental abnormality in the transition of the fetal to adult zone, resulting in glucocorticoid and mineralocorticoid deficiency. The etiology of HHG involves a combined and variable deficiency of hypothalamic GnRH secretion and/or pituitary responsiveness to GnRH resulting in low LH, FSH and testosterone. Treatment with exogenous gonadotropins generally does not induce spermatogenesis. Animal models indicate that DAX1 also plays a critical role in testis development and function. As a nuclear receptor, DAX1 has been shown to function as a transcriptional repressor, particularly of pathways regulated by other nuclear receptors, such as steroidogenic factor 1 (SF1). In addition to reproductive tissues, DAX1 is also expressed at high levels in ES cells and plays a role in the maintenance of pluripotentiality. Here we review the clinical manifestations associated with DAX1 mutations as well as the evolving information about its function based on animal models and in vitro studies.

1 Follower
 · 
103 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background/Aims: Hepatocellular carcinoma (HCC) represents the most common type of liver cancer. DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1), an atypical member of the nuclear receptor family due to lack of classical DNA-binding domains, has been known for its fundamental roles in the development, especially in the sex determination and steroidogenesis. Previous studies also showed that DAX-1 played a critical role in endocrine and sex steroid-dependent neoplasms such as adrenocortical, pituitary, endometrial, and ovarian tumors. However, its biological roles in the development of HCC remain largely unexplored. Methods: Real-time PCR and Western blot were used to detect the expression of DAX-1 in HCC tissues and cell lines. Immunoprecipitation (IP) assay was used to show the interaction between DAX-1 and β-Catenin. Small interfering RNA (siRNA) was used to silence the expression of DAX-1. BrdU incorporation and Cell-cycle assays were used to detect the role of DAX-1 in HCC cells proliferation. Migration and invasion assays were carried out to test the metastasis ability of DAX-1 in HCC cells. Results: In the present study, we found that mRNA and protein levels of DAX-1 were down-regulated in HCC tissues and cell lines. Furthermore, overexpression of DAX-1 could inhibit while its knockdown using small interfering RNA promoted cell proliferation in several HCC cell lines. At the molecular level, we demonstrated that DAX-1 could interact with β-Catenin and attenuate its transcriptional activity. Conclusion: Therefore, our results suggest a previously unknown DAX-1/β-Catenin molecular network controlling HCC development. © 2014 S. Karger AG, Basel.
    Cellular Physiology and Biochemistry 08/2014; 34(3):734-742. DOI:10.1159/000363038 · 3.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract We report a novel NR0B1 mutation in a patient affected with X-linked adrenal hypoplasia congenita (X-AHC). The proband first presented with a generalized convulsion at 11 years, 4 months. His clinical and biochemical presentations were consistent with adrenal insufficiency. His basal 17-hydroxyprogesterone (17-OHP) level was not high, and the poor response in 17-OHP on ACTH stimulation test excluded congenital adrenal hyperplasia. At 14 years of age, he did not show any signs of puberty, with low levels of LH, FSH, and testosterone and unresponsiveness to lutenizing hormone releasing hormone stimulation test. Direct DNA sequencing revealed that the proband is hemizygous for a novel NR0B1 mutation (c.1177_1180delGGCC, p.Gly393Cysfs*4). The mother is the conductor of the mutation, which is likely pathogenic as the C-terminus truncated protein lacks the activation function-2 (AF2-TA) transactivation domain, which is highly conserved among members of the nuclear receptor superfamily.
    Journal of pediatric endocrinology & metabolism: JPEM 07/2014; 27(11-12). DOI:10.1515/jpem-2014-0161 · 0.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: microRNAs (miRNAs) are a class of short noncoding RNA molecules that have a critical role in the initiation and progression of types of human cancer, including prostate cancer. In the present study, the expression of miR-181 in prostate cancer tissues was evaluated and was demonstrated to be significantly upregulated in prostate cancer tissues compared with that in adjacent normal tissues. The results of in vitro MTT and BrdU incorporation assays, as well as cell-cycle analysis, indicated that miR-181 overexpression markedly promoted the proliferation of LNCaP cells. Furthermore, miR-181 overexpression was found to promote the progression of LNCaP tumor growth in nude mice. Mechanistic studies demonstrated that dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1), a negative regulator of androgen receptor in prostate cancer, was inhibited by miR-181 overexpression. Therefore, the results from the present study suggest that miR-181 functions as a growth-suppressive miRNA during prostate cancer development.
    Experimental and therapeutic medicine 10/2014; 8(4):1296-1300. DOI:10.3892/etm.2014.1846 · 0.94 Impact Factor

Preview

Download
9 Downloads
Available from