A novel stop-loss DAX1 variant affecting its protein-interaction with SF1 precedes the adrenal hypoplasia congenital with rare spontaneous precocious puberty and elevated hypothalamic-pituitary-gonadal/adrenal axis responses.

Abstract

The case study unveils the likely mechanism of a novel stop-loss DAX1 variant preceding the prolonged precocious puberty in the adrenal hypoplasia congenital (AHC) boy. A boy aged five years and nine months initially examined for the primary adrenal insufficiency symptoms. Next-generation sequencing confirmed the X-linked inheritance of a novel stop-loss DAX1 variant: c.1411T>C/p.Ter471Gln associated with AHC in the patient. The patient was subjected to a brief clinical follow-up from 11 to 15.1 years of age. The effect of the mutant-DAX1 variant (p.Ter471Gln) on DAX1-steroidogenic factor 1 (SF1) (protein-protein) interaction was studied by protein-protein docking using the ClusPro-online tool. At 5.9 yrs of age, the patient exhibited precocious puberty with the secondary sexual characteristics of Tanner 2 stage (of 9-14 yrs of age). The patient showed primary adrenal insufficiency with diminished cortisol concentrations at blood serum (25 ng/ml) and urine (3.55 μg/24 h) levels. Upon steroidal exposure, the patient showed normalized serum cortisol levels of 45-61 ng/ml. However, the precocious puberty got prolonged with the increased penis length of 8.5 cm and the bone age of 18 yrs old during the follow-up. The patient showed increased basal serum adrenocorticotropic hormone (110->2000 pg/ml) and follicle-stimulating hormone (18.4-22.3 mIU/ml) concentrations. Following an elevated hypothalamic-pituitary-gonadal axis activity witnessed upon gonarellin stimulation. Protein-protein docking confirmed a weaker interaction between the mutant-DAX1 (p.Ter471Gln) protein and the wild-SF1 protein. Overall, we hypothesize the weakened mutant-DAX1-SF1 (protein-protein) interaction could govern the prolonged precocious puberty augmented with the elevated hypothalamic-pituitary-gonadal/adrenal axis responses via SF1-induced neuronal nitric oxide synthetase activation in the patient.

• Authors: Haihua Yang, Haiyan Wei, Linghua Shen, Selvaa Kumar C, Qiong Chen, Yongxing Chen, Senthil Arun Kumar
• Journal: European journal of medical genetics (Eur J Med Genet) Vol. 64 Issue 5 Pg. 104192 (May 2021) ISSN: 1878-0849 [Electronic] Netherlands
• PMID: 33766795 (Publication Type: Case Reports, Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Codon, Nonsense
• DAX-1 Orphan Nuclear Receptor
• NR0B1 protein, human
• Steroidogenic Factor 1
• Adrenocorticotropic Hormone
• Follicle Stimulating Hormone

Topics

• Adolescent
• Adrenocorticotropic Hormone (blood)
• Binding Sites
• Codon, Nonsense
• DAX-1 Orphan Nuclear Receptor (chemistry, genetics, metabolism)
• Follicle Stimulating Hormone (blood)
• Humans
• Hypoadrenocorticism, Familial (genetics, pathology)
• Hypothalamo-Hypophyseal System (metabolism)
• Loss of Function Mutation
• Male
• Protein Binding
• Puberty, Precocious (genetics, pathology)
• Steroidogenic Factor 1 (metabolism)