Dominique Simon1, Ibrahima Ba2, Nancy Mekhail2, Emmanuel Ecosse2, Anne Paulsen2, Delphine Zenaty1, Muriel Houang2, Monique Jesuran Perelroizen2, Gian-Paolo de Filippo2, Mariacarolina Salerno2, Gilbert Simonin2, Rachel Reynaud2, Jean-Claude Carel1, Juliane Léger1, Nicolas de Roux1. 1. AP-HPService d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, Paris F-75019, FranceUniversité Paris DiderotSorbonne Paris Cité F-75019, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM)Unité 1141, DHU Protect, Paris F-75019, FranceAP-HPINSERM U1141, Laboratoire de Biochimie, Hôpital Robert Debré, 48 Boulevard Sérurier, Paris F-75019, FranceAP-HPExplorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, Paris F-75012, FranceCentre d'Endocrinologie Pédiatrique14 Rue du Rempart St-Etienne, Toulouse F-31000, FrancePediatric Endocrinology UnitGaetano Rummo Hospital, Benevento 82100, ItalyPediatric Endocrinology UnitFederico II University, Naples 80131, ItalyService de Pédiatrie MultidisciplinaireCentre de Référence des Maladies Rares d'Origine Hypophysaire, Assistance Publique-Hopitaux de Marseille (APHM), Hôpital de la Timone, Aix-Marseille Université, Marseille F-13385, France AP-HPService d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, Paris F-75019, FranceUniversité Paris DiderotSorbonne Paris Cité F-75019, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM)Unité 1141, DHU Protect, Paris F-75019, FranceAP-HPINSERM U1141, Laboratoire de Biochimie, Hôpital Robert Debré, 48 Boulevard Sérurier, Paris F-75019, FranceAP-HPExplorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, Paris F-75012, FranceCentre d'Endocrinologie Pédiatrique14 Rue du Rempart St-Etienne, Toulouse F-31000, FrancePediatric Endocrinology UnitGaetano Rummo Hospital, Benevento 82100, ItalyPediatric Endocrinology UnitFederico II University, Naples 80131, ItalyService de Pédiatrie MultidisciplinaireCentre de Référence des Maladies Rares d'Origine Hypophysaire, Assistance Publique-Hopitaux de Marseille (APHM), Hôpital de la T 2. AP-HPService d'Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Hôpital Robert Debré, Paris F-75019, FranceUniversité Paris DiderotSorbonne Paris Cité F-75019, FranceInstitut National de la Santé et de la Recherche Médicale (INSERM)Unité 1141, DHU Protect, Paris F-75019, FranceAP-HPINSERM U1141, Laboratoire de Biochimie, Hôpital Robert Debré, 48 Boulevard Sérurier, Paris F-75019, FranceAP-HPExplorations Fonctionnelles Endocriniennes, Hôpital Armand Trousseau, Paris F-75012, FranceCentre d'Endocrinologie Pédiatrique14 Rue du Rempart St-Etienne, Toulouse F-31000, FrancePediatric Endocrinology UnitGaetano Rummo Hospital, Benevento 82100, ItalyPediatric Endocrinology UnitFederico II University, Naples 80131, ItalyService de Pédiatrie MultidisciplinaireCentre de Référence des Maladies Rares d'Origine Hypophysaire, Assistance Publique-Hopitaux de Marseille (APHM), Hôpital de la Timone, Aix-Marseille Université, Marseille F-13385, France.
Abstract
CONTEXT AND OBJECTIVE: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic-pituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations. DESIGN: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients. RESULTS: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), P=0.01). CONCLUSIONS: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.
CONTEXT AND OBJECTIVE: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic-pituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations. DESIGN: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients. RESULTS:MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), P=0.01). CONCLUSIONS:MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.
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