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Updated: Jun 23, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
FDXR variants cause adrenal insufficiency and atypical sexual development
Emanuele Pignatti1,2, Jesse Slone3, María Ángeles Gómez Cano4,5
1Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, and.
Abstract:
Genetic defects affecting steroid biosynthesis cause cortisol deficiency and differences of sex development; among these defects are recessive mutations in the steroidogenic enzymes CYP11A1 and CYP11B, whose function is supported by reducing equivalents donated by ferredoxin reductase (FDXR) and ferredoxin. So far, mutations in the mitochondrial flavoprotein FDXR have been associated with a progressive neuropathic mitochondriopathy named FDXR-related mitochondriopathy (FRM), but cortisol insufficiency has not been documented. However, patients with FRM often experience worsening or demise following stress associated with infections. We investigated 2 female patients with FRM carrying the potentially novel homozygous FDXR mutation p.G437R with ambiguous genitalia at birth and sudden death in the first year of life; they presented with cortisol deficiency and androgen excess compatible with 11-hydroxylase deficiency. In addition, steroidogenic FDXR-variant cell lines reprogrammed from 3 patients with FRM fibroblasts displayed deficient mineralocorticoid and glucocorticoid production. Finally, Fdxr-mutant mice allelic to the severe p.R386W human variant showed reduced progesterone and corticosterone production. Therefore, our comprehensive studies show that human FDXR variants may cause compensated but possibly life-threatening adrenocortical insufficiency in stress by affecting adrenal glucocorticoid and mineralocorticoid synthesis through direct enzyme inhibition, most likely in combination with disturbed mitochondrial redox balance.
Insights
Genetic defects in ferredoxin reductase (FDXR) can cause life-threatening adrenal insufficiency, particularly during stress. This study reveals FDXR variants impair steroid production, leading to cortisol deficiency and potential demise in patients with FDXR-related mitochondriopathy.
Area of Science:
- Biochemistry
- Genetics
- Endocrinology
Background:
- Genetic defects in steroid biosynthesis cause cortisol deficiency and differences in sex development.
- Mutations in ferredoxin reductase (FDXR) cause FDXR-related mitochondriopathy (FRM), but cortisol insufficiency was not previously documented.
- Patients with FRM can experience severe illness or death during stress, such as infections.
Purpose of the Study:
- To investigate the role of FDXR variants in adrenal insufficiency.
- To determine if FDXR mutations contribute to cortisol deficiency in patients with FRM.
- To explore the mechanism by which FDXR variants affect steroidogenesis.
Main Methods:
- Genetic analysis of two female patients with FRM and a novel FDXR mutation (p.G437R).
- Steroidogenic analysis of cell lines derived from FRM fibroblasts.
- Phenotypic analysis of Fdxr-mutant mice.
Main Results:
- The investigated patients presented with ambiguous genitalia, cortisol deficiency, and androgen excess, suggesting 11-hydroxylase deficiency.
- FDXR-variant cell lines showed deficient mineralocorticoid and glucocorticoid production.
- Fdxr-mutant mice exhibited reduced progesterone and corticosterone synthesis.
Conclusions:
- Human FDXR variants can cause compensated, yet potentially life-threatening, adrenocortical insufficiency under stress.
- These variants likely impair adrenal glucocorticoid and mineralocorticoid synthesis via direct enzyme inhibition and disturbed mitochondrial redox balance.
- FDXR mutations should be considered in the differential diagnosis of adrenal insufficiency, especially in patients with FRM or during stressful conditions.
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