Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency

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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.

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Figure 1: NNT loss increases the levels of mitochondrial ROS and apoptosis.


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We would like to thank J. Altmüller for running samples on a Genome Analyzer IIx, G. Nürnberg for performing the linkage analysis and the NHLBI GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison, including the Lung GO Sequencing Project (HL-102923), the Womens Health Initiative (WHI) Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010). This study was approved by the Outer North East London Research Ethics Committee (09/H0701/12). Affected individuals and/or their parents gave written informed consent to DNA studies at the outset of the study. This work has been supported by the Medical Research Council UK (New Investigator Research Grant G0801265 to L.A.M., Clinical Research Training Fellowship Grant G0901980 to C.R.H. and Project Grant G0700767 to P.J.K.).

Author information

L.A.M., A.J.L.C., P.J.K. and J.P.C. conceived and designed the experiments and jointly supervised the research. E.M., J.K., L.G., C.R.H., F.W. and L.A.M. performed the experiments. P.N., P.F. and E.M. analyzed the data and performed the statistical analysis. N.P.M., R.B. and H.N.S. contributed reagents and clinical information. L.A.M., A.J.L.C. and E.M. wrote the manuscript.

Correspondence to Adrian J L Clark.

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Supplementary Methods, Supplementary Tables 1 and 2 and Supplementary Figures 1–6 (PDF 3615 kb)

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Meimaridou, E., Kowalczyk, J., Guasti, L. et al. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet 44, 740–742 (2012) doi:10.1038/ng.2299

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