Normal Function
The NNT gene provides instructions for making an enzyme called nicotinamide nucleotide transhydrogenase. This enzyme is found embedded in the inner membrane of structures called mitochondria, which are the energy-producing centers of cells. This enzyme helps produce a substance called NADPH, which is involved in removing potentially toxic molecules called reactive oxygen species that can damage DNA, proteins, and cell membranes. Nicotinamide nucleotide transhydrogenase is found throughout the body, but it is particularly abundant in the hormone-producing adrenal and thyroid glands, heart, kidneys, and fatty tissue.
Health Conditions Related to Genetic Changes
Familial glucocorticoid deficiency
At least 25 mutations in the NNT gene have been found to cause familial glucocorticoid deficiency. This condition is characterized by potentially life-threatening low blood glucose (hypoglycemia), recurrent infections, and skin coloring darker than that of other family members (hyperpigmentation). The features of familial glucocorticoid deficiency are caused by an inability of the adrenal glands to produce a group of hormones called glucocorticoids, which play a role in many functions in the body. NNT gene mutations account for approximately 10 percent of cases of this condition.
Most of the mutations that cause familial glucocorticoid deficiency change single protein building blocks (amino acids) in the nicotinamide nucleotide transhydrogenase enzyme. These mutations impair the enzyme's ability to produce NADPH, leading to an increase in reactive oxygen species in the adrenal glands. Over time, these toxic molecules can impair the function of adrenal gland cells and lead to the death of those cells (apoptosis), diminishing the production of glucocorticoids. A shortage of these hormones impairs blood glucose regulation, immune system function, and other cellular functions, leading to the signs and symptoms of familial glucocorticoid deficiency.
It is unclear why NNT gene mutations seem to only affect adrenal gland function. Researchers suggest that individuals with familial glucocorticoid deficiency caused by NNT gene mutations could develop problems in other tissues over time as reactive oxygen species exert their harmful effects.
More About This Health ConditionOther Names for This Gene
- energy-linked transhydrogenase
- GCCD4
- NAD(P) transhydrogenase
- NAD(P) transhydrogenase, mitochondrial
- NADP transhydrogenase
- NADPH transferase
- nicotinamide adenine dinucleotide phosphate + transhydrogenase
- NNTM_HUMAN
- pyridine nucleotide transhydrogenase
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Meimaridou E, Hughes CR, Kowalczyk J, Guasti L, Chapple JP, King PJ, Chan LF, Clark AJ, Metherell LA. Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013 May 22;371(1-2):195-200. doi: 10.1016/j.mce.2012.12.010. Epub 2012 Dec 29. Citation on PubMed
- Meimaridou E, Kowalczyk J, Guasti L, Hughes CR, Wagner F, Frommolt P, Nurnberg P, Mann NP, Banerjee R, Saka HN, Chapple JP, King PJ, Clark AJ, Metherell LA. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet. 2012 May 27;44(7):740-2. doi: 10.1038/ng.2299. Citation on PubMed or Free article on PubMed Central
- Prasad R, Kowalczyk JC, Meimaridou E, Storr HL, Metherell LA. Oxidative stress and adrenocortical insufficiency. J Endocrinol. 2014 Jun;221(3):R63-73. doi: 10.1530/JOE-13-0346. Epub 2014 Mar 12. Citation on PubMed or Free article on PubMed Central
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