Identification and Analysis of a Novel NR0B1 Mutation in Late-Onset Adrenal Hypoplasia Congenita and Hypogonadism

Yutaka Hasegawa; Yoshihiko Takahashi; Yuichiro Kezuka; Wataru Obara; Yoichiro Kato; Shukuko Tamura; Ken Onodera; Toshie Segawa; Tomoyasu Oda; Marino Sato; Koji Nata; Takamasa Nonaka; Yasushi Ishigaki

doi:10.1210/jendso/bvaa176

Identification and Analysis of a Novel NR0B1 Mutation in Late-Onset Adrenal Hypoplasia Congenita and Hypogonadism

J Endocr Soc. 2020 Nov 13;5(2):bvaa176. doi: 10.1210/jendso/bvaa176. eCollection 2021 Feb 1.

Authors

Affiliations

¹ Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan.
² Division of Structural Biology, Department of Pharmaceutical Sciences, Iwate Medical University, Yahaba, Japan.
³ Thermo Fisher Scientific, Life Technologies Japan Ltd., Tokyo, Japan.
⁴ Department of Urology, School of Medicine, Iwate Medical University, Yahaba, Japan.
⁵ Division of Medical Biochemistry, School of Pharmacy, Iwate Medical University, Yahaba, Japan.

Abstract

Objective: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency and hypogonadotropic hypogonadism (HHG) caused by mutations of the NR0B1/DAX1 gene. We aimed to search for the presence of any NR0B1/DAX1 gene mutations in a referred patient and to further characterize the phenotypes of the identified mutation.

Case presentation: Herein, we report a Japanese patient with a novel missense mutation of the NR0B1/DAX1 gene resulting in adult-onset AHC and HHG. The patient was referred with diffuse skin pigmentation at 28 years of age, presented partial adrenal insufficiency and had undiagnosed incomplete HHG. Urological examination revealed severe oligospermia and testicular microlithiasis.

Results: The NR0B1/DAX1 gene mutation was identified by exome sequencing as a novel missense mutation (c.884A>T, p.Leu295His). We conducted in silico modeling of this mutant NR0B1/DAX1 protein (p.Leu295His) which affected the conserved hydrophobic core of the putative ligand-binding domain (LBD). In addition, functional analysis revealed that this mutant showed a decreased ability as a transcriptional repressor to suppress target genes, such as STAR and LHB. Furthermore, this mutant showed functionally impaired repression of steroidogenesis in human adrenocortical H295R cells.

Conclusions: We identified a novel missense mutation of the NR0B1/DAX1 gene in a patient suffering from late-onset AHC and HHG, who presented with oligospermia and testicular microlithiasis. This mutant NR0B1/DAX1 protein was found to have reduced repressor activity, according to in vitro studies, clinically consistent with the patient's phenotypic features.

Keywords: NR0B1; adrenal hypoplasia congenita; cortisol; hypogonadotropic hypogonadism; steroidogenic acute regulatory protein (STAR); testicular microlithiasis.