A novel homozygous mutation of the nicotinamide nucleotide transhydrogenase gene in a Japanese patient with familial glucocorticoid deficiency

Yamaguchi, Rie Shigetomi; Kato, Fumiko; Hasegawa, Tomonobu; Katsumata, Noriyuki; Fukami, Maki; Matsui, Toshiharu; Nagasaki, Keisuke; Ogata, Tsutomu

doi:10.1507/endocrj.ej13-0024

Cited by 20 publications

(18 citation statements)

References 9 publications

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“…4A). This is in accordance with the literature, where the minimum NNT, adrenal and extra-adrenal defects age at diagnosis is 3 days (12) and the median age at onset is 12 months for the 29 patients for whom data are available (9,11,12,13,15,16). Unlike the data by Jazayeri et al (2015), our data suggest earlier onset in patients with global adrenal deficiency compared with those with isolated glucocorticoid deficiency ( Fig.…”

Section: Discussionsupporting

confidence: 93%

“…It is clear that NNT mutations can result in global adrenal deficiency. In the literature and comparably to 14 of our patients, 5 families were recently described with mineralocorticoid deficiency present at onset and 3 others with elevated renin or electrolyte imbalance (11,12,13,16). Our patient 3 had salt wasting at age 15, although aldosterone requirements normally decrease throughout life (30).…”

Section: Discussionsupporting

confidence: 68%

“…Twelve more families have been reported (12 additional mutations), some with mineralocorticoid defects (11,12,13,14,15,16).…”

Section: Introductionmentioning

confidence: 99%

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NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

Roucher‐Boulez

Mallet-Motak

Samara-Boustani³

et al. 2016

European Journal of Endocrinology

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Objective: Nicotinamide nucleotide transhydrogenase (NNT), one of the several genes recently discovered in familial glucocorticoid deficiencies (FGD), is involved in reactive oxygen species detoxification, suggesting that extra-adrenal manifestations may occur, due to the sensitivity to oxidative stress of other organs rich in mitochondria. Here, we sought to identify NNT mutations in a large cohort of patients with primary congenital adrenal insufficiency without molecular etiology and evaluate the degree of adrenal insufficiency and onset of extra-adrenal damages. Methods: Sanger or massive parallel sequencing of NNT and patient monitoring. Results: Homozygous or compound heterozygous NNT mutations occurred frequently (26%, 13 unrelated families, 18 patients) in our cohort. Seven new mutations were identified: p.Met337Val, p.Ala863Glu, c.3G>A (p.Met1?), p.Arg129*, p.Arg379*, p.Val665Profs*29 and p.Ala704Serfs*19. The most frequent mutation, p.Arg129*, was found recurrently in patients from Algeria. Most patients were diagnosed belatedly (8-18 months) after presenting severe hypoglycemia; others experiencing stress conditions were diagnosed earlier. Five patients also had mineralocorticoid deficiency at onset. One patient had congenital hypothyroidism and two cryptorchidism. In follow-up, we noticed gonadotropic and genitalia impairments (precocious puberty, testicular inclusions, interstitial Leydig cell adenoma, azoospermia), hypothyroidism and hypertrophic cardiomyopathy. Intrafamilial phenotype heterogeneity was also observed. Conclusions: NNT should be sequenced, not only in FGD, but also in all primary adrenal insufficiencies for which the most frequent etiologies have been ruled out. As NNT is involved in oxidative stress, careful follow-up is needed to evaluate mineralocorticoid biosynthesis extent, and gonadal, heart and thyroid function.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 68%

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NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

Roucher‐Boulez

Mallet-Motak

Samara-Boustani³

et al. 2016

European Journal of Endocrinology

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“…Thus, NNT deficiency should be considered in the differential diagnosis of infantile adrenal failure presenting with combined glucocorticoid and mineralocorticoid deficiencies, and not only with apparently isolated glucocorticoid deficiency as previously described (2,3).…”

Section: Discussionmentioning

confidence: 85%

“…Mutations of the NNT gene have been recently implicated in familial glucocorticoid deficiency (2,3). In the present study, we describe the long-term clinical course of a NNT-deficient 20-year-old patient with combined adrenal failure who had developed testicular adrenal rest tumor and precocious puberty.…”

Section: Introductionmentioning

confidence: 92%

Combined adrenal failure and testicular adrenal rest tumor in a patient with nicotinamide nucleotide transhydrogenase deficiency

Hershkovitz

Arafat

Loewenthal

et al. 2015

Journal of Pediatric Endocrinology and Metabolism

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Molecular Genetics of Inherited Glucocorticoid Deficiency

Meimaridou

Kowalczyk

Metherell

2014

Encyclopedia of Life Sciences

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Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by isolated glucocorticoid deficiency and resistance of the adrenal cortex to adrenocorticotropic hormone (ACTH) action. Technological advances in genetics have contributed to our better understanding of the disease. Deoxyribonucleic acid (DNA) sequencing technology has given insight into the genetic cause of more than 60% of FGD cases, and revealed intersecting phenotypes with other adrenal insufficiency disorders. Defects have been recognised in the ACTH receptor ( MC2R ) and its accessory protein ( MRAP ), in the mitochondrial cholesterol transfer protein STAR, in MCM4 essential for DNA stability and repair and in NNT and TXNRD2 , essential for redox homoeostasis/detoxification of ROS. The remaining causes are yet to be elucidated and using next generation sequencing tools could incriminate additional pathways responsible for the onset of the disease. Key Concepts: Glucocorticoid deficiency is a feature of many adrenal disorders with overlapping clinical presentations. In most adrenal insufficiency disorders glucocorticoid deficiency is accompanied by mineralocorticoid deficiency. Technological advances in genetics have accelerated our understanding of the genetic causes of such diseases. Defects in novel pathways including those responsible for DNA stability and repair and those essential for redox homoeostasis/detoxification of ROS have recently been implicated in the pathogenesis of glucocorticoid deficiency. 40% of isolated glucocorticoid deficiency remains of unknown aetiology.

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A novel homozygous mutation of the nicotinamide nucleotide transhydrogenase gene in a Japanese patient with familial glucocorticoid deficiency

Cited by 20 publications

References 9 publications

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects

Combined adrenal failure and testicular adrenal rest tumor in a patient with nicotinamide nucleotide transhydrogenase deficiency

Molecular Genetics of Inherited Glucocorticoid Deficiency

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