Novel corticosteroid-binding globulin variant that lacks steroid binding activity.

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Corticosteroid-binding globulin (CBG) is crucial for regulating glucocorticoid bioavailability.
• Inherited deficiencies in CBG are rare, with few causative mutations documented.

Observation:

• A novel homozygous mutation (c.776g>t) in the CBG (SERPINA6) gene was identified in a patient with hypotension and fatigue.
• This mutation leads to a p.Gly237Val substitution, potentially affecting the steroid-binding site of CBG.
• Homozygous carriers exhibited undetectable CBG binding capacity and very low total serum cortisol, but normal free cortisol levels.

Findings:

• The identified CBG variant results in a complete loss of steroid-binding activity.
• Individuals with the mutation show significantly reduced total serum cortisol levels.
• Increased ultradian cortisol pulsatility was observed exclusively in the symptomatic patient.

Implications:

• This novel CBG variant provides insights into the structure-function relationship of the CBG steroid-binding site.
• Normal free cortisol levels despite low total cortisol highlight the body's compensatory mechanisms.
• Altered cortisol pulsatility may be a key factor in the symptomatology of CBG deficiency, influencing glucocorticoid signaling.