ESPE2024 Free Communications Adrenals and HPA Axis 2 (6 abstracts)
A deep intronic splice variant of CYP11B1 is the most common in Caucasian patients with 11-beta hydroxylase deficiency: functional, clinical and hormonal findings in 36 families
Clément Janot 1,2,3 , Delphine Mallet 1 , Aude Brac-De-La-Perrière 4 , Jérôme Bertherat 5 , Frédéric Brioude 6 , Audrey Cartault 7 , Mélanie Daval-Cote 8 , Stéphanie Espiard 9 , Muriel Houang 6 , Hervé Lefebvre 10 , Laetitia Martinerie 11 , Anne Mayer 12 , Harmony Mazoyer 13 , Catherine Pienkowski 7 , Virginie Ribault 14 , Yves Morel 1 , Ingrid Plotton 1,2,3 & Florence Roucher-Boulez 1,2,3
1Hospices Civils de Lyon, LBMMS, Service de Biochimie et Biologie moléculaire, Centre de Biologie et de Pathologie Est, Bron cedex F-69677, France. 2Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon F-69008, France. 3Stem-Cell and Brain Research Institute (SBRI), Inserm U1208, 69675 Bron Cedex, France. 4Service d'Endocrinologie, de Diabétologie et des Maladies Métaboliques A, Groupement Hospitalier Est, Hospices Civils de Lyon, Fédération d’Endocrinologie, Hôpital Louis Pradel, Bron, France. 5Department of Endocrinology, Hôpital Cochin, AP-HP, Paris, France. 6Sorbonne Université, APHP, Hôpital Armand Trousseau, Explorations Fonctionnelles Endocriniennes, Paris, France. 7Service d’Endocrinologie Pédiatrique, Centre Hospitalier Universitaire de Toulouse, Toulouse, France. 8Hospices Civils de Lyon, Groupement Hospitalier Est, Service d’Endocrinologie pédiatrique, Bron, France. 9Service d’Endocrinologie, Diabétologie et Maladies Métaboliques, Hôpitaux Universitaires de Lille, Lille, France. 10Department of Endocrinology, Univ Rouen Normandie, INSERM, NORDIC UMR 1239, CHU Rouen, Rouen F-76000, France. 11Endocrinologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, Hôpital Universitaire Robert-Debré, Paris 75019, France. 12Service d’endocrinologie, Savoie CHMS Hospital, F-73000 Chambéry, France. 13Centre Hospitalier de Dunkerque, Dunkerque, France. 14Service de Pédiatrie, CHU de Caen, F-14000 Caen, France
Background and Aims: Congenital adrenal hyperplasia (CAH) resulting from 11β-hydroxylase deficiency (11OHD) is a rare autosomal recessive (AR) disorder due to mutations in CYP11B1. Consequences are decreased cortisol secretion, elevated plasma levels of ACTH, and accumulation of steroid precursors causing abnormally high androgen synthesis and hypertension. High levels of 11-desoxycortisol provides diagnosis with certainty. However, in a cohort of 222 patients, some had only one or no identified variation in CYP11B1. The aims of this retrospective multicenter study was to identify the molecular hit, confirm the pathogenic impact of a novel splice variant, and to provide phenotypic insights and genotype correlation in 36 families.
Patients and Methods: Forty-four 11OHD patients throughout French territory were included. A potential pathogenic intronic variation was identified and impact on RNA splicing was studied by “minigene” study. Presence and severity of 46,XX DSD at birth, pseudopubertal signs and age of apparition, blood pressure status, as well as plasmatic 11-desoxycortisol, 17-hydroxyprogesterone and delta-4-androstenedione were retrospectively collected.
Results and Discussion: The same deep intronic variation NM_000497.4(CYP11B1): c.954+148C>G was identified in 11 patients at a homozygous state and in 29 at a compound heterozygous state (fifteen among them had a previously described severe second variant (p.Q19*, p.P94L, p.R141Q, p.T318M, p.Q356X, p.R448H, and c.954 G>C)). Minigene RNA sequencing in HeLa cells showed a major alternative 148bp longer mRNA in mutated condition, with an abnormal adding of intron 5 region and a shift in reading frame. Hormonal assay after ACTH stimulation showed that 11-desoxycortisol was >100nmol/L in 96% and >230nmol/L in 93% of patients, while 17-hydroxyprogesterone excluded 21-hydroxylase deficiency. Analysis of subgroups according to genotype showed that baseline 11-desoxycortisol was lower in c.954+148C>G homozygous patients than in other severe variants homozygous patients (P = 0.026), and similarly for baseline 17-hydroxyprogesterone et delta-4-androstenedione. As the phenotype sould be given by the milder variation in AR disorders, we hypothesized that the splice variant rules the phenotype homogeneously in all homozygous and compound heterozygous patients. Proportions of high blood pressure (25% and 29%) and 46,XX virilized DSD (85 and 87%) were homogenous between both groups (P >0.6), but pseudopubertal signs appeared significantly later in homozygous than in compound heterozygous (P = 0.003). To sum up, intronic regions needs to be explored and we described here the most frequent variation of CYP11B1 in 36 Caucasian families with classical 11OHD, which is correlated with less high 11-desoxycortisol levels and later pseudopubertal onset.
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