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Endocrine Abstracts (2016) 44 P27 | DOI: 10.1530/endoabs.44.P27

SFEBES2016 Poster Presentations Adrenal and Steroids (41 abstracts)

Structural analysis of nicotinamide nucleotide transhydrogenase (NNT) genetic variants causing adrenal disorders

Lou Metherell 1 , José Afonso Guerra-Assunção 2 , Michael Sternberg 3 & Alessia David 3


1Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK; 2Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK; 3Centre for Integrative System Biology and Bioinformatics, Imperial College London, London, UK.


Nicotinamide nucleotide transhydrogenase (NNT) is an integral protein of the inner mitochondrial membrane and plays a major role in maintaining the redox balance by catalysing the trans-hydrogenation between NADH and NADP+ and proton translocation across the mitochondrial membrane.

Genetic variants in NNT have recently been reported in patients with familial glucocorticoid deficiency (FGD), combined mineralocorticoid and glucocorticoid deficiency and combined adrenal failure and testicular adrenal rest tumours. Moreover, knockout animal models suggest that NNT is involved in the pathogenesis of diabetes mellitus and obesity. Impaired NNT activity is also thought to be involved in the aging process and the development of neurological disorders and cancer.

In this study, we generated a 3D structural model of human NNT (H-NNT) by homology modelling using bacterial NNT as templates. We identified key structural and functional residues in H-NNT, such as those participating in NAD binding and in H-NNT homodimerization. Moreover, we mapped 14 amino acid substitutions causing adrenal disorders and 6 rare genetic variants reported in the ExAC database. This new model allowed us to demonstrate that deleterious variants affect H-NNT structure by altering its structure (p.Gly200Ser, p.Thr357Ala, p.Tyr388Ser, p.Pro437Leu, p.Ala533Val, p.Leu977Pro), its ability to dimerize (p.Phe215Ser, p.His365Pro), its ability to bind NAD (p.Ser193Asn) or NADP (p.Ala1008Pro and p.Asn1009Lys) or its ability to correctly fold within the mitochondrial inner membrane (p.Gly664Arg, p.Gly678Arg, p.Gly862Asp). Without the 3D H-NNT model, molecular mechanisms could only be identified for the two variants located in the NADP binding site.

In conclusion, availability of a 3D H-NNT model allowed us to decipher the mechanisms by which genetic variants causing adrenal disease affect NNT structure and function. Structural biology can provide valuable information on the structure-function relationship of proteins, and integration of genetic analysis with protein 3D modelling can greatly enhance prioritization and interpretation of human genetic variants.

Volume 44

Society for Endocrinology BES 2016

Brighton, UK
07 Nov 2016 - 09 Nov 2016

Society for Endocrinology 

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