FDXR variants cause adrenal insufficiency and atypical sexual development.

Autor:	Pignatti E; Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, and.; Department of Biomedical Research, University of Bern, Bern, Switzerland., Slone J; Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA., Gómez Cano MÁ; Department of Pediatrics, Endocrinology Unit, and.; Unidad de Dismorfología y Genética (UDISGEN), 12 de Octubre University Hospital, Madrid, Spain., Campbell TM; Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA., Vu J; Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA., Sauter KS; Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, and.; Department of Biomedical Research, University of Bern, Bern, Switzerland., Pandey AV; Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, and.; Department of Biomedical Research, University of Bern, Bern, Switzerland., Martínez-Azorín F; Grupo de Enfermedades Raras, Mitocondriales y Neuromusculares (ERMN), Instituto de Investigación Hospital 12 de Octubre (imas12), E-28041 Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, E-28041 Madrid, Spain., Alonso-Riaño M; Pathology Department, 12 de Octubre University Hospital, Madrid, Spain., Neilson DE; Division of Genetics and Metabolism, Department of Child Health, The University of Arizona College of Medicine, Phoenix, Arizona, USA., Longo N; Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA., du Toit T; Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, and.; Department of Biomedical Research, University of Bern, Bern, Switzerland.; Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., Voegel CD; Department of Biomedical Research, University of Bern, Bern, Switzerland.; Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., Huang T; Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA., Flück CE; Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, and.; Department of Biomedical Research, University of Bern, Bern, Switzerland.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2024 Jun 17; Vol. 9 (14). Date of Electronic Publication: 2024 Jun 17.
DOI:	10.1172/jci.insight.179071
Abstrakt:	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.
Databáze:	MEDLINE
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