Abstract
Abstract Disclosure: E. Pignatti: None. J. Slone: None. M. Gomez-Cano: None. T.M. Campbell: None. J. Vu: None. K. Sauter: None. A.V. Pandey: None. M. Alonso-Riaño: None. F. Martínez-Azorín: None. D. Neilson: None. N. Longo: None. T. Du Toit: None. C.D. Voegel: None. T. Huang: None. C.E. Flueck: Consulting Fee; Self; Novo Nordisk. Grant Recipient; Self; Novo Nordisk, Sandoz, Pfizer, Inc., Merck. Speaker; Self; Sandoz. Background. Biallelic variants in the mitochondrial flavoprotein ferredoxin—NADP(+)-reductase (FDXR) have been associated with a progressive neuropathic mitochondriopathy named FDXR-Related Mitochondriopathy (FRM). FRM patients often experience worsening or demise following stress, but the cause is unclear. Ambiguous genitalia at birth have now been observed in some FRM patients. As FDXR is an essential partner for several steroid enzymes, we explored the impact of FDXR variants on steroid biosynthesis. Methods. To investigate whether the abnormal stress response of many FRM patients is caused by glucocorticoid deficiency, and whether observed ambiguous genitalia is related to androgen excess, we investigated the impact of FDXR variants on adrenal steroidogenesis. Clinical, genetic, biochemical, and functional studies were performed in index patients, steroidogenic cell lines reprogrammed from patient fibroblasts, and a novel disease mouse model. Results. Two paradigmatic female FRM patients carrying novel homozygous FDXR mutation p.G437R with ambiguous genitalia at birth and sudden death in the first year of life had cortisol deficiency and androgen excess compatible with 11-hydroxylase deficiency. Steroidogenic FDXR-variant cells lines reprogrammed from three patients’ fibroblasts also displayed deficient mineralocorticoid and glucocorticoid production. Likewise, Fdxr-variant mice allelic to the severe p.R386W human variant, showed reduced progesterone and corticosterone production. Conclusions. Our comprehensive studies show that FDXR variants in FRM patients 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. Presentation: 6/1/2024
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
