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Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress
  1. Ariella Weinberg-Shukron1,2,
  2. Abdulsalam Abu-Libdeh3,
  3. Fouad Zhadeh4,5,
  4. Liran Carmel4,
  5. Aviram Kogot-Levin6,
  6. Lara Kamal5,
  7. Moien Kanaan5,
  8. Sharon Zeligson1,
  9. Paul Renbaum1,
  10. Ephrat Levy-Lahad1,2,
  11. David Zangen3
  1. 1Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel
  2. 2Hebrew University Hadassah Medical School, Jerusalem, Israel
  3. 3Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
  4. 4Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel
  5. 5Hereditary Research Laboratory, Bethlehem University, Bethlehem, Palestine
  6. 6Diabetes Unit, Department of Internal Medicine, Hadassah University Hospital, Jerusalem, Israel
  1. Correspondence to Professor David Zangen, Division of Pediatric Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem 91240, Israel; zangend{at}hadassah.org.il

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.

Methods and 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.

  • Adrenal disorders
  • Clinical genetics
  • Endocrinology
  • Genetics
  • Molecular genetics

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