Apparent mineralocorticoid excess: type I and type II

Area of Science:

• Endocrinology
• Genetics
• Hypertension Research

Background:

• Apparent mineralocorticoid excess (AME) is an inherited hypertension characterized by hypokalemia and low renin, despite normal aldosterone.
• It results from a deficiency in the enzyme 11 beta-hydroxydehydrogenase (11 beta-HSD), which normally inactivates cortisol.
• This deficiency allows cortisol to act as a potent mineralocorticoid, binding to the mineralocorticoid receptor.

Purpose of the Study:

• To investigate the genetic basis of Apparent Mineralocorticoid Excess (AME).
• To identify mutations in the 11 beta-HSD enzyme gene responsible for AME.
• To understand the molecular mechanisms underlying cortisol metabolism defects in AME.

Main Methods:

• Biochemical analysis of urinary cortisol and cortisone metabolites, including the THF/THE ratio.
• Genetic analysis, including gene sequencing of 11 beta-HSD isoenzymes in affected individuals.
• Functional studies of mutant 11 beta-HSD sequences to assess enzyme activity.

Main Results:

• Mutations in the gene for the NAD-dependent 11 beta-HSD isoenzyme (type 2) were identified in patients with AME.
• These mutations, including point mutations and deletions, resulted in minimal or absent enzyme activity.
• A biochemical marker, an increased urinary ratio of tetrahydrocortisol (THF) to tetrahydrocortisone (THE), was observed in most patients.

Conclusions:

• Mutations in the 11 beta-HSD type 2 gene are the cause of Apparent Mineralocorticoid Excess (AME).
• This discovery establishes AME as a single-gene cause of human hypertension.
• Understanding the genetic basis of AME aids in diagnosis and potential therapeutic strategies.