Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency

Abstract

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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

References

  1. Clark, A.J. et al. Best Pract. Res. Clin. Endocrinol. Metab. 23, 159–165 (2009).

    CAS  Article  PubMed  Google Scholar 

  2. Metherell, L.A. et al. Nat. Genet. 37, 166–170 (2005).

    CAS  Article  PubMed  Google Scholar 

  3. Metherell, L.A. et al. J. Clin. Endocrinol. Metab. 94, 3865–3871 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Arkblad, E.L. et al. Free Radic. Biol. Med. 38, 1518–1525 (2005).

    CAS  Article  PubMed  Google Scholar 

  5. Toye, A.A. et al. Diabetologia 48, 675–686 (2005).

    CAS  Article  PubMed  Google Scholar 

  6. Freeman, H. et al. Biochem. Soc. Trans. 34, 806–810 (2006).

    CAS  Article  PubMed  Google Scholar 

  7. Yin, F., Sancheti, H. & Cadenas, E. Biochim. Biophys. Acta 1817, 401–409 (2012).

    CAS  Article  PubMed  Google Scholar 

  8. Dezso, Z. et al. BMC Biol. 12, 49 (2008).

    Article  Google Scholar 

  9. Su, A.I. et al. Proc. Natl. Acad. Sci. USA 99, 4465–4470 (2002).

    CAS  Article  Google Scholar 

  10. Walker, J.R. et al. Genome Res 14, 742–749 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Cooray, S.N. et al. Endocr. Dev. 13, 99–116 (2008).

    CAS  Article  PubMed  Google Scholar 

  12. Hirano, M. et al. Proc. Natl. Acad. Sci. USA 103, 2298–2303 (2006).

    CAS  Article  PubMed  Google Scholar 

  13. Storr, H.L. et al. Mol. Endocrinol. 23, 2086–2094 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Huebner, A. et al. Mol. Cell. Biol. 26, 1879–1887 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Adrian J L Clark.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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). https://doi.org/10.1038/ng.2299

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2299

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing