NNT – Familial Glucocorticoid Deficiency

Familial glucocorticoid deficiency (FGD; MONDO_0008733) is a rare autosomal recessive disorder characterized by isolated cortisol insufficiency despite elevated ACTH levels. Pathogenic variants in nicotinamide nucleotide transhydrogenase (NNT) underlie FGD type 4, accounting for approximately 5–10% of unsolved cases of FGD. The association between biallelic NNT loss-of-function and FGD is supported by multiple independent reports across diverse populations and concordant functional studies.

Genetic evidence includes compound heterozygous mutations identified in two non-consanguineous siblings (c.211C>T (p.Arg71Ter) and a 4-bp intronic duplication activating a 69-bp pseudoexon) segregating with disease in one pedigree (PMID:25459914), and homozygous frameshift or nonsense variants (e.g., c.1259dup (p.His421SerfsTer4) in a Dutch patient (PMID:26548497), c.644T>C (p.Phe215Ser) in a Japanese patient (PMID:26309815), and the founder p.Gly200Ser variant in Palestinian families (PMID:26070314)). In total, over 23 unrelated probands and at least 6 affected relatives have been reported with segregating NNT variants.

The variant spectrum encompasses early truncating alleles (nonsense, frameshift), canonical splice-site disruptions, missense substitutions affecting conserved residues, and intronic duplications causing pseudoexon activation. To date, more than 20 distinct pathogenic alleles have been described in FGD patients, with no clear genotype–phenotype correlation regarding age of onset or severity.

Functional studies in patient cells and model systems demonstrate that NNT deficiency leads to impaired mitochondrial NADPH production, increased reactive oxygen species (ROS) accumulation, and deficient antioxidant defenses. Mononuclear blood cells homozygous for p.Gly866Asp exhibit elevated ROS, decreased glutathione levels, and reduced mitochondrial mass under basal and oxidative stress conditions (PMID:36478070). In H295R adrenocortical carcinoma cells, CRISPR/Cas9-mediated NNT knockdown impairs steroidogenic enzyme expression and reduces cortisol and aldosterone secretion, linking redox imbalance directly to adrenal steroidogenesis.

Mechanistically, biallelic loss-of-function in NNT disrupts mitochondrial redox homeostasis, leading to oxidative damage of adrenocortical cells and deficient cortisol biosynthesis. The AR inheritance and consistent functional concordance fulfill criteria for a Strong gene–disease association under ClinGen standards.

Key Take-Home: Biallelic NNT pathogenic variants cause FGD type 4 via loss of mitochondrial NADPH-dependent antioxidant function, and genetic testing for NNT mutations enables early diagnosis, family counseling, and timely glucocorticoid replacement.

References

• The Journal of Clinical Endocrinology & Metabolism • 2015 • NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency. PMID:25459914
• European Journal of Medical Genetics • 2015 • A novel homozygous insertion and review of published mutations in the NNT gene causing familial glucocorticoid deficiency (FGD). PMID:26548497
• BBA Clinical • 2015 • Impact of a novel homozygous mutation in nicotinamide nucleotide transhydrogenase on mitochondrial DNA integrity in a case of familial glucocorticoid deficiency. PMID:26309815
• Journal of Medical Genetics • 2015 • Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress. PMID:26070314
• The Journal of Clinical Endocrinology & Metabolism • 2023 • Nicotinamide Nucleotide Transhydrogenase Is Essential for Adrenal Steroidogenesis: Clinical and In Vitro Lessons. PMID:36478070

Evidence Based Scoring (AI generated)