RESUMO
DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia congenital critical region on X chromosome gene 1), a key sex determinant in various species, plays a vital role in gonad differentiation and development and controls spermatogenesis. However, the identity and function of DAX1 are still unclear in bivalves. In the present study, we identified a DAX1 (designed as Tc-DAX1) gene from the boring giant clam Tridacna crocea, a tropical marine bivalve. The full length of Tc-DAX1 was 1877 bp, encoding 462 amino acids, with a Molecular weight of 51.81 kDa and a theoretical Isoelectric point of 5.87 (pI). Multiple sequence alignments and phylogenetic analysis indicated a putative ligand binding domain (LBD) conserved regions clustered with molluscans DAX1 homologs. The tissue distributions in different reproductive stages revealed a dimorphic pattern, with the highest expression trend in the male reproductive stage, indicating its role in spermatogenesis. The DAX1 expression data from embryonic stages shows its highest expression profile (P < 0.05) in the zygote stage, followed by decreasing trends in the larvae stages (P > 0.05). The localization of DAX1 transcripts has also been confirmed by whole mount in situ hybridization, showing high positive signals in the fertilized egg, 2, and 4-cell stage, and gastrula. Moreover, RNAi knockdown of the Tc-DAX1 transcripts shows a significantly lower expression profile in the ds-DAX1 group compared to the ds-EGFP group. Subsequent histological analysis of gonads revealed that spermatogenesis was affected in a ds-DAX1 group compared to the ds-EGFP group. All these results indicate that Tc-DAX1 is involved in the spermatogenesis and early embryonic development of T. crocea, providing valuable information for the breeding and aquaculture of giant clams.
Assuntos
Bivalves , Gônadas , Masculino , Animais , Filogenia , Gônadas/metabolismo , Espermatogênese/genética , Alinhamento de Sequência , Bivalves/genética , Receptor Nuclear Órfão DAX-1/genética , Receptor Nuclear Órfão DAX-1/metabolismoRESUMO
46,XY gonadal dysgenesis (GD) is a disorder of sex development due to incomplete gonadal differentiation into testes, resulting in female to ambiguous external genitalia. Duplications at the Xp21.2 locus involving the NR0B1 (DAX1) gene have previously been associated with 46,XY GD. More recently, a complex structural variant not directly involving NR0B1 has been reported in 46,XY GD illustrating that the mechanism of how copy number variants (CNVs) at Xp21.2 may cause 46,XY gonadal dysgenesis is not yet fully understood. Here, we report on three families in which a duplication involving the NR0B1 gene was detected in the context of prenatal screening. This is the first report of duplications involving NR0B1 in three phenotypically normal males in two families. Fertility problems were present in one adult male carrier. The data reported here from an unbiased screening population broaden the phenotype associated with CNVs involving NR0B1, and this may aid clinicians in counseling and decision making in the prenatal context.
Assuntos
Receptor Nuclear Órfão DAX-1 , Disgenesia Gonadal 46 XY , Adulto , Feminino , Humanos , Masculino , Receptor Nuclear Órfão DAX-1/genética , Transtornos do Desenvolvimento Sexual/genética , Variações do Número de Cópias de DNA , Disgenesia Gonadal 46 XY/genética , FenótipoRESUMO
Adrenal hypoplasia congenita, attributed to NR0B1 pathogenic variants, accounts for more than 50% of the incidence of primary adrenal insufficiency in children. Although more than 250 different deleterious variations have been described, no genotype-phenotype correlation has been defined to date. We report a case of an adopted boy who reported the onset of an adrenal crisis at 2 weeks of age, requiring replacement therapy with mineralocorticoids and glucocorticoids for 4 months. For 3 years, he did well without treatment. At almost 4 years of age, the disorder was restarted. A long follow-up showed the evolution of hypogonadotropic hypogonadism. Molecular studies on NR0B1 revealed a novel and deleterious deletion-insertion-inversion-deletion complex rearrangement sorted in the 5'-3' direction, which is described as follows: (1) deletion of the intergenic region (between TASL and NR0B1 genes) and 5' region, (2) insertion of a sequence containing 37 bp at the junction of the intergenic region of the TASL gene and a part of exon 1 of the NR0B1 gene, (3) inversion of a part of exon 1, (4) deletion of the final portion of exon 1 and exon 2 and beginning of the 3'UTR region, (5) maintenance of part of the intergenic sequence (between genes MAGEB1 and NR0B1, telomeric sense), (6) large posterior deletion, in the same sense. The path to molecular diagnosis was challenging and involved several molecular biology techniques. Evaluating the breakpoints in our patient, we assumed that it was a nonrecurrent rearrangement that had not yet been described. It may involve a repair mechanism known as nonhomologous end-joining (NHEJ), which joins two ends of DNA in an imprecise manner, generating an "information scar," represented herein by the 37 bp insertion. In addition, the local Xp21 chromosome architecture with sequences capable of modifying the DNA structure could impact the formation of complex rearrangements.
Assuntos
Insuficiência Adrenal , Receptor Nuclear Órfão DAX-1 , Pré-Escolar , Humanos , Masculino , Insuficiência Adrenal/genética , Insuficiência Adrenal/patologia , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/congênito , Receptor Nuclear Órfão DAX-1/genética , Seguimentos , Estudos de Associação Genética/métodos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Hipoadrenocorticismo Familiar/genética , Mutação/genética , Fenótipo , Recém-Nascido , AdolescenteRESUMO
X-linked adrenal hypoplasia congenita (AHC) is caused predominantly by mutations in the NR0B1 (DAX1) gene. Among these, X-linked AHC due to a large deletion of NR0B1 is extremely rare. In Korea, the first case was reported in 2005, and there have been no further documented cases since then. Herein, we report a unique case of X-linked AHC caused by an entire gene deletion that includes the NR0B1 gene and seven other genes. A seven-day-old boy presented to a pediatric endocrine clinic with prolonged postnatal jaundice, skin hyperpigmentation, hyponatremia, and hyperkalemia, suggestive of an adrenal crisis. In genetic analysis, next-generation sequencing panel for congenital adrenal hyperplasia (CAH) showed no variants. However, chromosomal microarray results revealed large deletion of Xp21.2 (29,655,007_30,765,126) including eight protein-coding genes (NR0B1, IL1RAPL1, GK, MAGEB1-4, TASL). In cases of atypical adrenal insufficiency and genetically undiagnosed CAH, NR0B1-related AHC should be suspected, as Xp21 deletion is very rare and not detected in NGS, making microarray the best option for genetic diagnosis.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Criança , Humanos , Hipoadrenocorticismo Familiar/genética , Deleção de Genes , Mutação , Receptor Nuclear Órfão DAX-1/genéticaRESUMO
Dax1 (Nr0b1; Dosage-sensitive sex reversal-adrenal hypoplasia congenital on the X-chromosome gene-1) is an important component of the transcription factor network that governs pluripotency in mouse embryonic stem cells (ESCs). Functional evaluation of alternative splice variants of pluripotent transcription factors has shed additional insight on the maintenance of ESC pluripotency and self-renewal. Dax1 splice variants have not been identified and characterized in mouse ESCs. We identified 18 new transcripts of Dax1 with putative protein-coding properties and compared their protein structures with known Dax1 protein (Dax1-472). The expression pattern analysis showed that the novel isoforms were cotranscribed with Dax1-472 in mouse ESCs, but they had transcriptional heterogeneity among single cells and the subcellular localization of the encoded proteins differed. Cell function experiments indicated that Dax1-404 repressed Gata6 transcription and functionally replaced Dax1-472, while Dax1-38 and Dax1-225 partially antagonized Dax1-472 transcriptional repression. This study provided a comprehensive characterization of the Dax1 splice variants in mouse ESCs and suggested complex effects of Dax1 variants in a self-renewal regulatory network.
Assuntos
Receptor Nuclear Órfão DAX-1 , Células-Tronco Embrionárias , Células-Tronco Embrionárias Murinas , Animais , Camundongos , Diferenciação Celular , Células-Tronco Embrionárias/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Células-Tronco Embrionárias Murinas/metabolismo , Fatores de Transcrição/metabolismo , Receptor Nuclear Órfão DAX-1/genética , Receptor Nuclear Órfão DAX-1/metabolismoRESUMO
Coupling the release of pituitary hormones to the developmental stage of the oocyte is essential for female fertility. It requires estrogen to restrain kisspeptin (KISS1)-neuron pulsatility in the arcuate hypothalamic nucleus, while also exerting a surge-like effect on KISS1-neuron activity in the AVPV hypothalamic nucleus. However, a mechanistic basis for this region-specific effect has remained elusive. Our genomic analysis in female mice demonstrate that some processes, such as restraint of KISS1-neuron activity in the arcuate nucleus, may be explained by region-specific estrogen receptor alpha (ERα) DNA binding at gene regulatory regions. Furthermore, we find that the Kiss1-locus is uniquely regulated in these hypothalamic nuclei, and that the nuclear receptor co-repressor NR0B1 (DAX1) restrains its transcription specifically in the arcuate nucleus. These studies provide mechanistic insight into how ERα may control the KISS1-neuron, and Kiss1 gene expression, to couple gonadotropin release to the developmental stage of the oocyte.
Assuntos
Receptor Nuclear Órfão DAX-1 , Receptor alfa de Estrogênio , Hipotálamo , Kisspeptinas , Animais , Feminino , Camundongos , Núcleo Arqueado do Hipotálamo/metabolismo , Estradiol/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Hipotálamo/metabolismo , Kisspeptinas/genética , Kisspeptinas/metabolismo , Receptor Nuclear Órfão DAX-1/genética , Receptor Nuclear Órfão DAX-1/metabolismoRESUMO
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.
Assuntos
Insuficiência Adrenal , Hipogonadismo , Humanos , Hipoadrenocorticismo Familiar/genética , Insuficiência Adrenal/diagnóstico por imagem , Insuficiência Adrenal/genética , Éxons , Hipogonadismo/genética , Receptor Nuclear Órfão DAX-1/genética , Tomografia Computadorizada por Raios XRESUMO
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. The dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1, NR0B1), is an orphan nuclear receptor that acts as a transcriptional co-repressor of various genes. In this study, we identified the role of DAX-1 in APAP-induced liver injury using hepatocyte-specific Dax-1 knockout (Dax-1 LKO) mice. Mouse primary hepatocytes were used as a comparative in vitro study. APAP overdose led to decreased plasma alanine aminotransferase and aspartate aminotransferase levels in Dax-1 LKO mice compared to C57BL/6J (WT) controls, accompanied by reduced liver necrosis. The expression of the genes encoding the enzymes catalyzing glutathione (GSH) synthesis and metabolism and antioxidant enzymes was increased in the livers of APAP-treated Dax-1 LKO mice. The rapid recovery of GSH levels in the mitochondrial fraction of APAP-treated Dax-1 LKO mice led to reduced reactive oxygen species levels, resulting in the inhibition of the prolonged JNK activation. The hepatocyte-specific DAX-1 deficiency increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) compared with WT controls after APAP administration. These results indicate that DAX-1 deficiency in hepatocytes protects against APAP-induced liver injury by Nrf2-regulated antioxidant defense.
Assuntos
Antipiréticos , Doença Hepática Induzida por Substâncias e Drogas , Receptor Nuclear Órfão DAX-1 , Fator 2 Relacionado a NF-E2 , Acetaminofen/toxicidade , Alanina Transaminase/metabolismo , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Proteínas Correpressoras/metabolismo , Receptor Nuclear Órfão DAX-1/genética , Glutationa/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Receptores Nucleares Órfãos/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
An appropriate balance between testicular testosterone and estradiol is required for spermatogenesis. Excess estradiol is often identified in the semen and serum of infertile men; however, the mechanisms behind this observation remain unclear. This study indicates the relationship between heat stress and aromatase synthesis in Leydig cells. We used R2C rat Leydig tumor cells, which can synthesize both testosterone and estradiol. Aromatase transcription was regulated by the Pâ ¡ promoter with or without heat stress. Heat stress at 40 °C increased aromatase expression and decreased testosterone to estradiol ratio and nuclear DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), which is a suppressor of steroidogenic factor 1 (SF-1). Leptomycin B and KPT-185, a nuclear export inhibitor, prevented nuclear DAX-1 deficiency induced by heat stress and inhibited aromatase transcription. These results indicate that heat stress interferes with DAX-1-SF-1 interaction and induces SF-1-dependent aromatase transcription.
Assuntos
Aromatase , Fatores de Transcrição , Masculino , Ratos , Animais , Fator Esteroidogênico 1/genética , Aromatase/genética , Aromatase/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Ligação a DNA/metabolismo , Receptor Nuclear Órfão DAX-1/genética , Testosterona , Resposta ao Choque Térmico , EstradiolRESUMO
OBJECTIVES: Mutations in the dosage-sensitive sex reversal-AHC critical region on the X chromosome, gene 1 (DAX-1, officially NR0B1), cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). Salt-losing adrenal insufficiency usually occurs during the neonatal period or early childhood. We report a novel non-stop variant of NR0B1 in two siblings and their unusual clinical course. CASE PRESENTATION: The proband was a boy who presented with an unusual form of AHC with neonatal onset of growth failure and mild salt loss, but without cutaneous pigmentation or plasma ACTH elevation. His 4-year-old elder brother had been growing healthily, but carried an AHC diagnosis. A non-stop variant of NR0B1 (p.*471K) was demonstrated in the patients and their mother. CONCLUSIONS: We identified a novel non-stop variant of NR0B1 in two siblings. Mild salt loss associated with hyperkalemia is a crucial diagnostic clue for AHC, even without apparent symptoms of glucocorticoid deficiency.
Assuntos
Insuficiência Adrenal , Hipogonadismo , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/genética , Idoso , Pré-Escolar , Receptor Nuclear Órfão DAX-1/genética , Humanos , Hipoadrenocorticismo Familiar/genética , Hipogonadismo/genética , Recém-Nascido , Masculino , Mutação , IrmãosRESUMO
Nuclear receptor subfamily 0 group B member 1 gene (NR0B1) encodes an orphan nuclear receptor that plays a critical role in the development and regulation of the adrenal gland and hypothalamic-pituitary-gonadal axis. In this study, we report a novel mutation in NR0B1 that led to adult-onset adrenal hypoplasia congenita (AHC) and pubertal development failure in a male adult. Clinical examinations revealed hyponatremia, elevated adrenocorticotropic hormone levels, reduced testosterone and gonadotropin levels, and hyper-responses to gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests. Whole-exome sequencing and Sanger sequencing were performed to identify the potential causes of AHC. Candidate variants were shortlisted based on the X-linked recessive models. Sequence analyses identified a novel hemizygous variant of c.1034delC in exon 1 of NR0B1 at Xp21.2, resulting in a frameshift mutation and premature stop codon formation. The c.1034delC/p.Pro345Argfs*27 in the NR0B1 gene was detected in the hemizygous state in affected males and in the heterozygous state in healthy female family carriers. These results expand the clinical features of AHC as well as the mutation profile of the causative gene NR0B1. Further studies are needed to elucidate the biological effects of the mutation on the development and function of the adrenal gland and the hypothalamic-pituitary-gonadal axis.
Assuntos
Insuficiência Adrenal , Doenças Genéticas Ligadas ao Cromossomo X , Hipogonadismo , Insuficiência Adrenal/genética , Adulto , Receptor Nuclear Órfão DAX-1/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Hipoadrenocorticismo Familiar/genética , Hipogonadismo/genética , Masculino , TestosteronaRESUMO
Background: NR0B1 pathogenic variants can cause congenital adrenal hypoplasia or primary adrenal insufficiency in early childhood usually associated with hypogonadotropic hypogonadism. NR0B1 is necessary for organogenesis of the adrenal cortex and to maintain normal spermatogenesis. In humans, restoration of fertility in patients carrying NR0B1 pathogenic variants is challenging. Objective: The aim of the study was to investigate the clinical, hormonal, histological, spermiological, and molecular genetic characteristics of a cohort of patients with NR0B1 pathogenic variants, monitored for fertility preservation. Patients: We included five patients, including four teenagers, with NR0B1 pathogenic or likely pathogenic variants. They all had primary adrenal insufficiency and were receiving replacement therapy with glucocorticoids and mineralocorticoids. Patients received recombinant follicle-stimulating hormone and recombinant human chorionic gonadotropin in order to induce spermatogenesis. Combined gonadotropin treatment was initiated between 13 years and 15 years and 6 months for the four teenagers and at 31 years and 2 months for the only adult. Physical and hormonal assessments were performed just before starting gonadotropin treatment. After 12 months of gonadotropin treatment, physical examination and hormonal assessments were repeated, and semen analyses were performed. If no sperm cells were observed in at least 2 semen collections at 3-month interval, testicular biopsy for testicular sperm extraction was proposed. Results: Bilateral testicular volume increased from 8 ml (interquartile range, 6-9) to 12 ml (10-16) after gonadotropin treatment. Inhibin B levels were relatively stable: 110 ng/L (46-139) before and 91 ng/L (20-120) at the end of gonadotropin treatment. Azoospermia was observed in all semen analyses for all cases during gonadotropin treatment. Three patients agreed to testicular biopsy; no mature sperm cells could be retrieved in any. Conclusion: We characterized a cohort of patients with NR0B1 pathogenic or likely pathogenic variants for fertility preservation by recombinant gonadotropin treatment, which began either at puberty or in adulthood. No sperm cells could be retrieved in semen samples or testicular biopsy even after gonadotropin treatment, indicating that gonadotropin treatment, even when started at puberty, is ineffective for restoring fertility.
Assuntos
Doença de Addison , Hipogonadismo , Doença de Addison/tratamento farmacológico , Adolescente , Adulto , Pré-Escolar , Gonadotropina Coriônica/uso terapêutico , Receptor Nuclear Órfão DAX-1/genética , Humanos , Hipogonadismo/tratamento farmacológico , Masculino , Substâncias para o Controle da Reprodução , Espermatozoides , TestículoRESUMO
Premature ovarian insufficiency (POI) is one of the main causes of female premature infertility. POI is a genetically heterogeneous disorder with a complex molecular etiology; as such, the genetic causes remain unknown in the majority of patients. Therefore, this study aimed to identify mutations and characterize the associated molecular contribution of gonadogenesis-determinant genes to POI. Genomic assays, including PCR-SSCP and Sanger sequencing, followed by in silico analyses were used to investigate the underpinnings of ovarian deficiency in 11 women affected by POI. Large deletions and nucleotide insertions and duplications were excluded by PCR. Thirteen genetic variants were identified in the WT1 (c.213G>T, c.609T>C, c.873A>G, c.1122G>A), NR0B1 (c.353C>T, c.425G>A), NR5A1 (c.437G>C, IVS4-20C>T), LHX9 (IVS2-12G>C, IVS3+13C>T, c.741T>C), ZNF275 (c.969C>T), and NRIP1 (c.3403C>T) genes. Seven novel genetic variants and five unpublished substitutions were identified. No genetic aberrations were detected in the ZFP92 and INSL3 genes. Each variant was genotyped using PCR-SSCP in 100 POI-free subjects, and their allelic frequencies were similar to the patients. These analyses indicated that allelic variation in the WT1, NR0B1, NR5A1, LHX9, ZFP92, ZNF275, INSL3, and NRIP1 genes may be a non-disease-causing change or may not contribute significantly to the genetics underlying POI disorders. Findings support the polygenic nature of this clinical disorder, with the SNVs identified representing only a probable contribution to the variability of the human genome.
Assuntos
Infertilidade Feminina , Insuficiência Ovariana Primária , Alelos , Estudos de Coortes , Receptor Nuclear Órfão DAX-1/genética , Feminino , Humanos , Infertilidade Feminina/genética , Proteínas com Homeodomínio LIM/genética , Masculino , Mutação , Mutação de Sentido Incorreto , Insuficiência Ovariana Primária/genética , Fator Esteroidogênico 1/genética , Fatores de Transcrição/genética , Proteínas WT1/genéticaRESUMO
OBJECTIVES: X-linked adrenal hypoplasia congenita (AHC) is characterized by adrenal insufficiency and hypogonadotropic hypogonadism. Herein, we report a rare case of X-linked AHC with central precocious puberty (CPP). CASE PRESENTATION: An 11-month-old male patient was found to have premature pubarche, enlargement of the penis, and frequent erection. LH and FSH levels after the GnRHa test were in the pubertal range. Direct sequencing revealed a heterozygous variant of the NR0B1 gene. The proband was treated with hydrocortisone and 9-alpha fludrocortisone because of the significantly elevated ACTH and renin activity. The secondary sexual characteristics relieved gradually. The serum testosterone and LH subsequently returned to the prepubertal range. The basal serum FSH values have been between 1.0 and 2.0 IU/L since the age of 2.25 years, with extremely low AMH levels beginning at 3 years. CONCLUSIONS: The clinical course of CPP with NR0B1 variant may be temporary. HPG axis status of X-linked AHC may probably be pleomorphic during the longitudinal follow-up.
Assuntos
Insuficiência Adrenal , Puberdade Precoce , Insuficiência Adrenal/genética , Pré-Escolar , Receptor Nuclear Órfão DAX-1/genética , Hormônio Foliculoestimulante , Seguimentos , Humanos , Hipoadrenocorticismo Familiar/genética , Lactente , Masculino , Mutação , Puberdade Precoce/tratamento farmacológico , Puberdade Precoce/genéticaRESUMO
Adrenal hypoplasia congenita (AHC) is a rare disorder of the adrenal gland due to mutations in the nuclear receptor superfamily 0, group B, member 1 (NR0B1) gene. It commonly presents with adrenal insufficiency and hypogonadotropic hypogonadism, but there is a wide variability in the age as well as the clinical phenotype at presentation. Also, the mechanism of pubertal abnormalities in this condition, which include not just delayed or absent pubertal development, but also precocious puberty in a small proportion of cases, is not clear. In this paper, three unrelated patients with 3 different mutations are described, who presented with variable age of onset of adrenal insufficiency, gonadal development, and puberty, highlighting the need for high index of suspicion of this condition in children presenting with atypical features of adrenal insufficiency.
Assuntos
Insuficiência Adrenal , Receptor Nuclear Órfão DAX-1 , Hipogonadismo , Mutação , Puberdade Precoce , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/genética , Receptor Nuclear Órfão DAX-1/genética , Humanos , Hipogonadismo/genética , Puberdade Precoce/genéticaRESUMO
X-linked adrenal hypoplasia congenita is a rare cause of primary adrenal insufficiency. Mutations in the NR0B1 gene cause a loss of function in the DAX1 receptor, which activates genes involved in the development and function of the hypothalamic-pituitary-gonadal axis. Objective: To describe a case of adrenal hypoplasia congenita secondary to a mutation in the NR0B1 gene and identified the differential diagnoses of the pediatric patient with adrenal insufficiency and hypogonadotropic hypogonadism. Clinical Case: A 4-year-old male patient with no relevant history and from a rural area was admitted to the emergency room due to a 15-days of emesis, asthenia, adynamia, myalgia, and ataxic gait. On the physical examination, hypotension, hyponatremia, and hyperkalemia, as well as mucosal hyperpigmentation and bilateral cryptorchidism were observed, therefore, adrenal crisis was diagnosed, starting fluid resuscitation with saline solution, hydrocortisone, and fludrocortisone, which stabilized the patient. Adrenal hyperplasia congenita, innate metabolic error, and infectious or autoimmune etiology were ruled out as etiology. A clinical exome test was performed which iden tified the variant c.1275A > T; p.Arg425Ser (Transcript ENST00000378970.5) in the NR0B1 gene consistent with X-linked adrenal hypoplasia congenita. Management of the patient continued with glucocorticoids and mineralocorticoids with favorable clinical course at 7 years of follow-up. Con clusion: A novel pathogenic variant associated with X-linked adrenal hypoplasia is described. Variants in the NR0B1 gene should be a differential diagnosis in a male patient with the association of primary adrenal insufficiency and hypogonadism.
Assuntos
Doença de Addison , Insuficiência Adrenal , Doenças Genéticas Ligadas ao Cromossomo X , Pré-Escolar , Humanos , Masculino , Doença de Addison/diagnóstico , Doença de Addison/genética , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/genética , Insuficiência Adrenal/congênito , Receptor Nuclear Órfão DAX-1/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Hipoadrenocorticismo Familiar/genética , MutaçãoRESUMO
A region of 160 kb at Xp21.2 has been defined as dosage-sensitive sex reversal (DSS) and includes the NR0B1 gene, considered to be the candidate gene involved in XY gonadal dysgenesis if overexpressed. We describe a girl with 46,XY partial gonadal dysgenesis carrying a 297 kb duplication at Xp21.2 upstream of NR0B1 initially detected by chromosomal microarray analysis. Fine mapping of the breakpoints by whole-genome sequencing showed a tandem duplication of TASL (CXorf21), GK and partially TAB3, upstream of NR0B1. This is the first description of an Xp21.2 duplication upstream of NR0B1 associated with 46,XY partial gonadal dysgenesis.
Assuntos
Disgenesia Gonadal 46 XY , Feminino , Humanos , Receptor Nuclear Órfão DAX-1/genética , Disgenesia Gonadal 46 XY/genéticaRESUMO
DAX1 plays an essential role in the differentiation and physiology of the Hypothalamic-Pituitary-Adrenal-Gonadal (HPAG) axis during embryogenesis. However, in adult tissues, in addition to the HPAG axis, evidence has not been found for its differential expression and function. We isolated the DAX1 cDNA to analyze its tissue localization and gene expression profiles in male and female hamsters' Harderian glands (HGs), Mesocricetus auratus. The isolated cDNA clone contains 1848 base pairs (bp), and a 1428-bp open reading frame (ORF) encodes a 476 amino acid protein. Sequence alignments and the phylogenetic tree display a relevant percentage of similarity with human (66%), rat (81%), and mouse (84%) sequences. In adult tissues, the mRNA distribution demonstrated that DAX1 is present in testis, ovaries, and male and female HGs. The highest expression profiles were identified in the adrenal glands, where females exhibit higher mRNA levels than males. The sexually dimorphic expression of DAX1 in adrenals suggests that its presence could be associated with regulating, functioning, and maintaining this endocrine tissue. These findings indicate that the DAX1 gene is limitedly expressed in adult tissues. In the HGs, we demonstrate the absence of sexually dimorphic gene expression. Our results suggest that DAX1 might have an additional physiological function outside of the HPAG axis, specifically in the HG, which may be required for the regulation of intracrine steroidogenesis, secretion, and maintenance of exocrine tissue.
Assuntos
Receptor Nuclear Órfão DAX-1/genética , Receptor Nuclear Órfão DAX-1/metabolismo , Glândula de Harder/metabolismo , Mesocricetus/genética , Mesocricetus/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , Receptor Nuclear Órfão DAX-1/química , Feminino , Masculino , Modelos Moleculares , Filogenia , Homologia de Sequência de Aminoácidos , TranscriptomaRESUMO
Copy number variations of several genes involved in the process of gonadal determination have been identified as a cause of 46,XY differences of sex development. We report a non-syndromic 14-year-old female patient who was referred with primary amenorrhea, absence of breast development, and atypical genitalia. Her karyotype was 47,XY,+mar/46,XY, and FISH analysis revealed the X chromosome origin of the marker chromosome. Array-CGH data identified a pathogenic 2.0-Mb gain of an Xp21.2 segment containing NR0B1/DAX1 and a 1.9-Mb variant of unknown significance from the Xp11.21p11.1 region. This is the first report of a chromosomal microarray analysis to reveal the genetic content of a small supernumerary marker chromosome detected in a 47,XY,+der(X)/46,XY karyotype in a non-syndromic girl with partial gonadal dysgenesis and gonadoblastoma. Our findings indicate that the mosaic presence of the small supernumerary Xp marker, encompassing the NR0B1/DAX1 gene, may have been the main cause of dysgenetic testes development, although the role of MAGEB and other genes mapped to the Xp21 segment could not be completely ruled out.