Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency.
Using targeted exome sequencing, we identified mutations in NNT, an antioxidant defense gene, in individuals with familial glucocorticoid deficiency. In mice with Nnt loss, higher levels of adrenocortical cell apoptosis and impaired glucocorticoid production were observed. NNT knockdown in a human adrenocortical cell line resulted in impaired redox potential and increased reactive oxygen species (ROS) levels. Our results suggest that NNT may have a role in ROS detoxification in human adrenal glands.
Centre for Endocrinology, Queen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Eirini
E
Meimaridou
Julia
J
Kowalczyk
Leonardo
L
Guasti
Claire R
CR
Hughes
Florian
F
Wagner
Peter
P
Frommolt
Peter
P
Nürnberg
Nicholas P
NP
Mann
Ritwik
R
Banerjee
H Nurcin
HN
Saka
J Paul
JP
Chapple
Peter J
PJ
King
Adrian J L
AJ
Clark
Louise A
LA
Metherell
D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism; D000309:Adrenal Insufficiency / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002675:Child, Preschool; D004931:Esophageal Achalasia / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D009250:NADP Transhydrogenases / Q000235:genetics*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D016415:Sequence Alignment
D000975:Antioxidants; D005938:Glucocorticoids; D017382:Reactive Oxygen Species; D009250:NADP Transhydrogenases