title: Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress.
abstract: BACKGROUND
  Familial glucocorticoid deficiency (FGD) reflects specific failure of adrenocortical glucocorticoid production in response to adrenocorticotropic hormone (ACTH). Most cases are caused by mutations encoding ACTH-receptor components (MC2R, MRAP) or the general steroidogenesis protein (StAR). Recently, nicotinamide nucleotide transhydrogenase (NNT) mutations were found to cause FGD through a postulated mechanism resulting from decreased detoxification of reactive oxygen species (ROS) in adrenocortical cells.
  
  
  RESULTS
  In a consanguineous Palestinian family with combined mineralocorticoid and glucocorticoid deficiency, whole-exome sequencing revealed a novel homozygous NNT_c.598 G>A, p.G200S, mutation. Another affected, unrelated Palestinian child was also homozygous for NNT_p.G200S. Haplotype analysis showed this mutation is ancestral; carrier frequency in ethnically matched controls is 1/200. Assessment of patient fibroblasts for ROS production, ATP content and mitochondrial morphology showed that biallelic NNT mutations result in increased levels of ROS, lower ATP content and morphological mitochondrial defects.
  
  
  CONCLUSIONS
  This report of a novel NNT mutation, p.G200S, expands the phenotype of NNT mutations to include mineralocorticoid deficiency. We provide the first patient-based evidence that NNT mutations can cause oxidative stress and both phenotypic and functional mitochondrial defects. These results directly demonstrate the importance of NNT to mitochondrial function in the setting of adrenocortical insufficiency.
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Ariella
authors.initials: A
authors.lastname: Weinberg-Shukron
authors.affiliation: Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Abdulsalam
authors.initials: A
authors.lastname: Abu-Libdeh
authors.affiliation: Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.
authors.forename: Fouad
authors.initials: F
authors.lastname: Zhadeh
authors.affiliation: Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Liran
authors.initials: L
authors.lastname: Carmel
authors.affiliation: Diabetes Unit, Department of Internal Medicine, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Aviram
authors.initials: A
authors.lastname: Kogot-Levin
authors.affiliation: Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.
authors.forename: Lara
authors.initials: L
authors.lastname: Kamal
authors.affiliation: Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine.
authors.forename: Moien
authors.initials: M
authors.lastname: Kanaan
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Zeligson
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.affiliation: Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
authors.affiliation: Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Zangen
mesh_terms: D018912:Arabs; D003241:Consanguinity; D005938:Glucocorticoids / Q000172:deficiency*; D006720:Homozygote; D006801:Humans; D008901:Mineralocorticoids / Q000172:deficiency*; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D009250:NADP Transhydrogenases / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D017422:Sequence Analysis, DNA
chemical_list: D005938:Glucocorticoids; D008901:Mineralocorticoids; D018161:Receptors, Mineralocorticoid; D009250:NADP Transhydrogenases
keywords: Adrenal disorders; Clinical genetics; Endocrinology; Genetics; Molecular genetics