Abstract

Congenital adrenal hyperplasia (CAH) is a rare X-linked recessive inherited disease that is considered a major cause of steroidogenesis disorder and is associated with variants or complete deletion of the NR0B1 gene. The DAX-1 protein (encoded by NR0B1) is a vertebrate-specific orphan nuclear receptor and is also a transcriptional factor for adrenal and reproductive development. CAH usually causes adrenal insufficiency in infancy and early childhood, leading to hypogonadotropic hypogonadism in adulthood; however, few adult cases have been reported to date. In this study, we examined a Chinese family with one adult patient with CAH, and identified a putative variant of NR0B1 gene via next-generation sequencing (NGS), which was confirmed with Sanger sequencing. A novel nonsense variant (c.265C>T) was identified in the NR0B1 gene, which caused the premature termination of DAX-1 at residue 89 (p.G89*). Furthermore, mutant NR0B1 gene displayed a partial DAX-1 function, which may explain the late pathogenesis in our case. Additionally, qPCR revealed the abnormal expression of four important genes identified from ChIP-seq, which were associated with energy homeostasis and steroidogenesis, and were influenced by the DAX-1 mutant. In addition, hormone disorders can be caused by DAX-1 mutant and partially recovered by siRNA of PPARGC1A. Herein, we identified a novel nonsense variant (c.265C>T) of NR0B1 in a 24-year-old Chinese male who was suffering from CAH. This mutant DAX-1 protein was found to have disordered energy homeostasis and steroidogenesis based on in vitro studies, which was clinically consistent with the patient’s phenotypic features.

Highlights

  • Congenital adrenal hyperplasia (CAH) is a rare X-linked recessive inherited disease that is considered a major cause of steroidogenesis disorder and is associated with variants or complete deletion of the NR0B1 gene

  • We found that the proband, a 24-year-old male, presented with skin hyperpigmentation, fatigue, vertigo, nausea, emaciation, vomiting, and poor sleep according to a clinical examination and the patient’s description

  • For the first time, we identified a novel nonsense variant located in NR0B1 with X-linked inheritance from a three-generation Han family by nextgeneration sequencing (NGS) analysis, which was further corroborated by Sanger sequencing (Fig. 1)

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Summary

Introduction

Congenital adrenal hyperplasia (CAH) is a rare X-linked recessive inherited disease that is considered a major cause of steroidogenesis disorder and is associated with variants or complete deletion of the NR0B1 gene. We identified a novel nonsense variant (c.265C>T) of NR0B1 in a 24-year-old Chinese male who was suffering from CAH This mutant DAX-1 protein was found to have disordered energy homeostasis and steroidogenesis based on in vitro studies, which was clinically consistent with the patient’s phenotypic features. Various novel variants associated with CAH have been reported to date, suggesting that the identification of gene variants in CAH could be a promising approach to diagnose ­CAH2–4 Patients with this disorder usually show signs and symptoms of adrenal insufficiency in early infancy or throughout childhood. Secreted hormones and related gene expression changes influenced by the DAX-1 mutant, which were partially recovered by silencing of PPARGC1A, implied that this NR0B1 variant caused CAH, providing a preliminary understanding of the potential molecular mechanism driving CAH. These findings provide a preliminary understanding of the potential molecular mechanism driving CAH and significantly advance our molecular understanding of the varietal spectrum of NR0B1 in the context of CAH

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