title: Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD).
abstract: BACKGROUND
  Classic ACTH resistance, due to disruption of ACTH signaling, accounts for the majority of cases of familial glucocorticoid deficiency (FGD). Recently FGD cases caused by mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase, have highlighted the importance of redox regulation in steroidogenesis.
  
  
  OBJECTIVE
  We hypothesized that other components of mitochondrial antioxidant systems would be good candidates in the etiology of FGD.
  
  
  METHODS
  Whole-exome sequencing was performed on three related patients, and segregation of putative causal variants confirmed by Sanger sequencing of all family members. A TXNRD2-knockdown H295R cell line was created to investigate redox homeostasis.
  
  
  METHODS
  The study was conducted on patients from three pediatric centers in the United Kingdom.
  
  
  METHODS
  Seven individuals from a consanguineous Kashmiri kindred, six of whom presented with FGD between 0.1 and 10.8 years, participated in the study.
  
  
  METHODS
  There were no interventions.
  
  
  METHODS
  Identification and functional interrogation of a novel homozygous mutation segregating with the disease trait were measured.
  
  
  RESULTS
  A stop gain mutation, p.Y447X in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 (TXNRD2) was identified and segregated with disease in this extended kindred. RT-PCR and Western blotting revealed complete absence of TXNRD2 in patients homozygous for the mutation. TXNRD2 deficiency leads to impaired redox homeostasis in a human adrenocortical cell line.
  
  
  CONCLUSIONS
  In contrast to the Txnrd2-knockout mouse model, in which embryonic lethality as a consequence of hematopoietic and cardiac defects is described, absence of TXNRD2 in humans leads to glucocorticoid deficiency. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans.
authors.affiliation: Centre for Endocrinology (R.P., L.F.C., C.R.H., J.C.K., M.O.S., A.J.L.C., H.L.S., L.A.M.), Queen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom; Inherited Cardiovascular Diseases Unit (J.P.K.), Department of Cardiology, Great Ormond St Hospital for Children, and Department of Paediatric Endocrinology (C.J.P.), Great Ormond St Hospital for Children, London WC1N 3JH, United Kingdom; and Department of Paediatric Endocrinology (N.N.), Luton and Dunstable University Hospital, Luton LU4 0DZ, United Kingdom.
authors.forename: Rathi
authors.initials: R
authors.lastname: Prasad
authors.forename: Li F
authors.initials: LF
authors.lastname: Chan
authors.forename: Claire R
authors.initials: CR
authors.lastname: Hughes
authors.forename: Juan P
authors.initials: JP
authors.lastname: Kaski
authors.forename: Julia C
authors.initials: JC
authors.lastname: Kowalczyk
authors.forename: Martin O
authors.initials: MO
authors.lastname: Savage
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Peters
authors.forename: Nisha
authors.initials: N
authors.lastname: Nathwani
authors.forename: Adrian J L
authors.initials: AJ
authors.lastname: Clark
authors.forename: Helen L
authors.initials: HL
authors.lastname: Storr
authors.forename: Louise A
authors.initials: LA
authors.lastname: Metherell
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000235:genetics*; D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D043202:Steroid Metabolism, Inborn Errors / Q000235:genetics*; D054482:Thioredoxin Reductase 2 / Q000235:genetics*
chemical_list: C516127:TXNRD2 protein, human; D054482:Thioredoxin Reductase 2