Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism

Nature ◽  
1994 ◽  
Vol 372 (6507) ◽  
pp. 672-676 ◽  
Author(s):  
Françoise Muscatelli ◽  
Tim M. Strom ◽  
Ann P. Walker ◽  
Elena Zanaria ◽  
Dominique Récan ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

scholarly journals A novel DAX1/NR0B1 mutation in a patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism

2012 ◽  
Vol 56 (8) ◽  
pp. 496-500 ◽  
Author(s):  
Claudilene Battistin ◽  
Hamilton Cabral de Menezes Filho ◽  
Sorahia Domenice ◽  
Mirian Yumie Nishi ◽  
Thais Della Manna ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Failure To Thrive ◽  
The Novel ◽  
Site Analysis ◽  
Adrenal Hypoplasia Congenita ◽  
Normal Individuals ◽  
Exon 1 ◽  
Adrenal Hypoplasia ◽  
Low Levels

We report a case of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to a novel DAX1 mutation. A 19-month-old boy with hyperpigmentation and failure to thrive came to our service for investigation. Three brothers of the patient had died due to adrenal failure, and a maternal cousin had adrenal insufficiency. Adrenoleukodystrophy was excluded. MRI showed normal pituitary and hypothalamus. Plasma hormone evaluation revealed high ACTH (up to 2,790 pg/mL), and low levels of androstenedione, DHEA-S, 11-deoxycortisol, and cortisol. At 14 years of age the patient was still prepubescent, his weight was 43.6 kg (SDS: -0.87) and his height was 161 cm (SDS: -0.36), with normal body proportions. In the GnRH test, basal and maximum values of LH and FSH were respectively 0.6/2.1 and < 1.0/< 1.0 U/L. Molecular investigation identified a novel mutation that consists of a deletion of codon 372 (AAC; asparagine) in exon 1 of DAX1. This mutation was not found in a study of 200 alleles from normal individuals. Prediction site analysis indicated that this alteration, located in the DAX1 ligand-binding domain, may damage DAX1 protein. We hypothesize that the novel (p.Asp372del) DAX1 mutation might be able to cause a disruption of DAX1 function, and is probably involved in the development of AHC and HH in this patient. Arq Bras Endocrinol Metab. 2012;56(8):496-500

scholarly journals Delayed-onset adrenal hypoplasia congenita and hypogonadotropic hypogonadism caused by a novel mutation in DAX1

2019 ◽  
Vol 48 (2) ◽  
pp. 030006051988215
Author(s):  
Siyue Liu ◽  
Libin Yan ◽  
Xinrong Zhou ◽  
Chen Chen ◽  
Daowen Wang ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Molecular Testing ◽  
Delayed Onset ◽  
Adrenal Hypoplasia Congenita ◽  
Congenital Adrenal Hypoplasia ◽  
Translation Start ◽  
Adrenal Hypoplasia ◽  
Relevant Family History ◽  
Mild Clinical Phenotype

In this study, we described a male who presented with delayed-onset adrenal hypoplasia congenita (AHC) and mild hypogonadotropic hypogonadism (HHG) without a relevant family history. A novel mutation in the DAX1 (dosage-sensitive sex reversal, congenital adrenal hypoplasia critical region on the X chromosome, gene 1) gene was shown to cause X-linked AHC and HHG. Genetic analysis revealed a novel nonsense mutation, c.154G > T (p.Glu52Term), in the DAX1 gene. Molecular testing demonstrated that the milder phenotype caused by this mutation was due to expression of a partially functional, amino-truncated DAX1 protein generated from an alternate in-frame translation start site (methionine at codon 83). This unusual case revealed a potential mechanism for a novel mutation that resulted in an unusual delayed-onset mild clinical phenotype. It expands the spectrum of adrenal hypoplasia congenita and hypogonadotropic hypogonadism.

Clinical and molecular characterization of five Spanish kindreds with X-linked adrenal hypoplasia congenita: atypical findings and a novel mutation in NR0B1

2015 ◽  
Vol 28 (9-10) ◽  
Author(s):  
Amaia Rodríguez Estévez ◽  
Gustavo Pérez-Nanclares ◽  
Joaquin Fernández-Toral ◽  
Francisco Rivas-Crespo ◽  
Juan P. López-Siguero ◽  
...  
Keyword(s):  
Molecular Level ◽  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Gene Mutations ◽  
Delayed Puberty ◽  
Salt Wasting ◽  
Adrenal Hypoplasia Congenita ◽  
Intrafamilial Variability ◽  
Adrenal Hypoplasia

AbstractX-linked adrenal hypoplasia congenita (AHC) is caused byTo characterize clinically and at the molecular level a cohort of Spanish patients with AHC.Nine boys (from five families) with AHC were screened forgene mutations were found in all analyzed patients, one of them being novel (p.Gln305*). One patient presented with preserved hypothalamic-pituitary-gonadal axis. Salt-wasting episodes, delayed puberty, and hypogonadotropic hypogonadism were common, although no association was observed between AHC phenotype and genetic mutations. None of the patients has had descendants.AHC phenotype cannot be predicted based on genetic results as there is no definite genotype-phenotype relationship, including intrafamilial variability. Nevertheless, genetic testing for

Novel mutations of DAX1 (NR0B1) in two Chinese families with X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism

2015 ◽  
Vol 28 (7-8) ◽  
Author(s):  
Guijun Qin ◽  
Hongfei Ji ◽  
Xialian Li ◽  
Xiaokun Ma ◽  
Danping Wang
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Coding Region ◽  
Novel Mutations ◽  
Chinese Families ◽  
Adrenal Hypoplasia Congenita ◽  
Adrenal Hypoplasia

AbstractTo analyze theTwo families with 4 affected males, 5 carrier females, and 4 unaffected males were investigated. Sequencing of the entire 1413-bp coding region ofTwo different novelTwo novel

Xp duplications and sex reversal

1995 ◽  
Vol 350 (1333) ◽  
pp. 291-296 ◽  
Keyword(s):  
Ovarian Development ◽  
Hypogonadotropic Hypogonadism ◽  
Sex Reversal ◽  
Nuclear Receptor Superfamily ◽  
Adrenal Hypoplasia Congenita ◽  
Male Phenotype ◽  
Adrenal Hypoplasia ◽  
Male To Female ◽  
Atypical Member ◽  
Functional Deficiency

Male to female sex reversal has been observed in individuals with duplications of the short arm of the X chromosome. The study of Xp duplicated patients demonstrated that sex reversal results from the presence of two active copies of the DSS (dosage sensitive sex reversal) locus. A double dosage of DSS disrupts testis formation whereas its absence is compatible with a male phenotype, suggesting a role for DSS in ovarian development and as a link between ovary and testis formation. DSS was localized to a 160 kb region of Xp21, overlapping the adrenal hypoplasia congenita locus. The search for expressed sequences in the DSS critical region led to the identification of two types of genes: the DAM family and DAX-1, an atypical member of the nuclear receptor superfamily. Although no function is currently known for DAM genes, functional deficiency for DAX-1 has been shown to be responsible for adrenal hypoplasia congenita and hypogonadotropic hypogonadism. The search for the DSS gene(s) is still open and both the DAM genes and DAX-1 represent DSS candidate genes.

scholarly journals Orphan Receptor DAX-1 Is a Shuttling RNA Binding Protein Associated with Polyribosomes via mRNA

2000 ◽  
Vol 20 (13) ◽  
pp. 4910-4921 ◽  
Author(s):  
Enzo Lalli ◽  
Kenji Ohe ◽  
Colette Hindelang ◽  
Paolo Sassone-Corsi
Keyword(s):  
Rna Binding ◽  
Hypogonadotropic Hypogonadism ◽  
Intracellular Localization ◽  
Significant Proportion ◽  
Binding Activity ◽  
Nuclear Hormone Receptor ◽  
Orphan Receptor ◽  
Adrenal Hypoplasia Congenita ◽  
Leydig Tumor Cells ◽  
Adrenal Hypoplasia

ABSTRACT The DAX-1 (NR0B1) gene encodes an unusual member of the nuclear hormone receptor superfamily which acts as a transcriptional repressor. Mutations in the human DAX-1 gene cause X-linked adrenal hypoplasia congenita (AHC) associated with hypogonadotropic hypogonadism (HHG). We have studied the intracellular localization of the DAX-1 protein in human adrenal cortex and mouse Leydig tumor cells and found it to be both nuclear and cytoplasmic. A significant proportion of DAX-1 is associated with polyribosomes and is found complexed with polyadenylated RNA. DAX-1 directly binds to RNA, two domains within the protein being responsible for cooperative binding activity and specificity. Mutations in DAX-1 found in AHC-HHG patients significantly impair RNA binding. These findings reveal that DAX-1 plays multiple regulatory roles at the transcriptional and posttranscriptional levels.

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