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

Florence Roucher-Boulez (1, 2) , Delphine Mallet-Moták (1) , Dinane Samara-Boustani (3) , Houweyda Jilani (1) , Asmahane Ladjouze (4) , Pierre François Souchon (5) , Dominique Simon (6) , Sylvie Nivot (7) , Claudine Heinrichs (8) , Maryline Ronze (9, 10) , Xavier Bertagna (11) , Laure Groisne (1) , Bruno Leheup (12, 13) , Naud-Saudreau Naud-Saudreau (14) , Gilles Blondin (14) , Christine Lefevre (15) , Laetitia Lemarchand (16) , Yves Morel (2, 1)

1 CHU Lyon
2 UCBL - Université Claude Bernard Lyon 1
3 Hôpital Necker - Enfants Malades [AP-HP]
4 Centre Hospitalier Universitaire de Bab-el-Oued
5 American Memorial Hospital (Reims)
6 Service d'Endocrinologie et Diabétologie Pédiatriques
7 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
8 Hôpital Universitaire des Enfants Reine Fabiola
9 Université médicale de Vienne, Autriche
10 CH Vienne - Centre Hospitalier de Vienne Lucien Hussel
11 UMR_S567 / UMR 8104 - Institut Cochin
12 Service de Génétique Médicale [CHRU Nancy]
13 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
14 CH Lorient - Centre Hospitalier de Lorient
15 Hôpital Jeanne de Flandres
16 Service de pédiatrie, Hopital Saint-Louis, La Rochelle

OBJECTIVE: NNT (nicotinamide nucleotide transhydrogenase), one of 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\textgreaterA (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 one hypertrophic cardiomyopathy. Intrafamilial phenotype heterogeneity was 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.

Mots clés: primary adrenal insufficiency; oxidative stress; nicotinamide nucleotide transhydrogenase; follow-up; massive parallel sequencing

Domaines: Sciences du Vivant [q-bio]; Endocrinologie et métabolisme

Florence Roucher-Boulez, Delphine Mallet-Moták, Dinane Samara-Boustani, Houweyda Jilani, Asmahane Ladjouze, et al.. NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects. European Journal of Endocrinology, 2016, 175, pp.73-84. ⟨10.1530/EJE-16-0056⟩. ⟨hal-01321410⟩