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Published on: December 9, 2015
ACTH resistance: genes and mechanisms
E Meimaridou1, C R Hughes, J Kowalczyk
1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Endocrine Development
|February 9, 2013
Summary
Familial glucocorticoid deficiency (FGD) is caused by new gene defects in MCM4 and NNT. These findings reveal novel genetic mechanisms underlying ACTH resistance and adrenal cortex stress sensitivity.
Area of Science:
- Endocrinology
- Genetics
- Molecular Biology
Background:
- Familial glucocorticoid deficiency (FGD) is a rare, genetically diverse disorder characterized by ACTH resistance.
- Previous genetic studies identified mutations in MC2R, MRAP, and STAR genes, affecting ACTH signaling and steroidogenesis.
- These defects disrupt ACTH ligand binding, receptor trafficking, or cholesterol transport for steroid hormone production.
Purpose of the Study:
- To identify novel genetic causes of familial glucocorticoid deficiency (FGD).
- To elucidate new pathogenetic mechanisms contributing to ACTH resistance.
- To understand the adrenal cortex's sensitivity to genomic and oxidative stress.
Main Methods:
- Genetic analysis of patients with familial glucocorticoid deficiency (FGD).
- Identification and characterization of mutations in novel genes.
- Investigation of the functional consequences of identified mutations on adrenal function.
Main Results:
- Novel gene defects were identified in mini-chromosome maintenance-deficient 4 homologue (MCM4) and nicotinamide nucleotide transhydrogenase (NNT) in FGD patients.
- MCM4 mutations implicate DNA replication and genome stability in FGD pathogenesis.
- NNT mutations suggest a role for the glutathione redox system and oxidative stress in adrenal dysfunction.
Conclusions:
- Mutations in MCM4 and NNT represent new genetic causes of familial glucocorticoid deficiency (FGD).
- These findings expand the known genetic basis of ACTH resistance.
- The adrenal cortex demonstrates significant sensitivity to DNA replication stress and oxidative damage, as indicated by these novel genetic defects.
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