M Muzza1, S Rabbiosi, M C Vigone, I Zamproni, V Cirello, M A Maffini, K Maruca, N Schoenmakers, L Beccaria, F Gallo, S-M Park, P Beck-Peccoz, L Persani, G Weber, L Fugazzola. 1. Department of Clinical Sciences and Community Health (M.M., V.C., M.A.M., P.B.-P., L.F.), University of Milan, and Endocrine Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Ca' Granda, 20122 Milan, Italy; Department of Pediatrics (S.R., M.C.V., I.Z., K.M., G.W.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 21032 Milan, Italy; Department of Clinical Sciences and Community Health (L.P.), University of Milan, Milan, and Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano, 20149 Milan, Italy; Department of Pediatrics (L.B.), A. Manzoni Hospital, 73100 Lecco, Italy; Metabolic Research Laboratories (N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Pediatrics (F.G.), Perrino Hospital, 72100 Brindisi, Italy; and Department of Clinical Genetics (S.-M.P.), Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
Abstract
CONTEXT: Mutations in the DUOX2 gene have been associated with transient or permanent congenital hypothyroidism due to a dyshormonogenic defect. OBJECTIVE: This study aimed to verify the prevalence of DUOX2 mutations and the associated clinical features in children selected by criteria supporting a partial iodide organification defect (PIOD). PATIENTS AND METHODS: Thirty children with PIOD-like criteria were enrolled and genotyped. A detailed clinical characterization was undertaken together with the functional analysis of the DUOX2 variations and the revision of the clinical and molecular data of the literature. RESULTS: In this large selected series, the prevalence of the DUOX2 mutations was high (37%). We identified 12 missense variants, one splice site, and three frameshift DUOX2 mutations. Functional analyses showed significant impairment of H2O2 generation with five missense variants. Stop-codon mutants were shown to totally abolish DUOX2 activity by nonsense-mediated RNA decay, exon skipping, or protein truncation. DUOX2 mutations, either mono- or biallelic, were most frequently associated with permanent congenital hypothyroidism. Moreover, the present data suggested that, together with goiter and PIOD, the most significant features to select patients for the DUOX2 analysis are the low free T4 and the high TSH concentrations at the first postnatal serum sampling, despite borderline blood spot TSH. Interestingly, the analysis of previously described DUOX2 mutated cases confirmed the validity of these findings. CONCLUSIONS: The defects in the peroxide generation system are common among congenital hypothyroidism patients with PIOD. The most robust clinical parameters for selecting patients for DUOX2 analysis have been identified, and several DUOX2 variants have been functionally characterized.
CONTEXT: Mutations in the DUOX2 gene have been associated with transient or permanent congenital hypothyroidism due to a dyshormonogenic defect. OBJECTIVE: This study aimed to verify the prevalence of DUOX2 mutations and the associated clinical features in children selected by criteria supporting a partial iodide organification defect (PIOD). PATIENTS AND METHODS: Thirty children with PIOD-like criteria were enrolled and genotyped. A detailed clinical characterization was undertaken together with the functional analysis of the DUOX2 variations and the revision of the clinical and molecular data of the literature. RESULTS: In this large selected series, the prevalence of the DUOX2 mutations was high (37%). We identified 12 missense variants, one splice site, and three frameshift DUOX2 mutations. Functional analyses showed significant impairment of H2O2 generation with five missense variants. Stop-codon mutants were shown to totally abolish DUOX2 activity by nonsense-mediated RNA decay, exon skipping, or protein truncation. DUOX2 mutations, either mono- or biallelic, were most frequently associated with permanent congenital hypothyroidism. Moreover, the present data suggested that, together with goiter and PIOD, the most significant features to select patients for the DUOX2 analysis are the low free T4 and the high TSH concentrations at the first postnatal serum sampling, despite borderline blood spot TSH. Interestingly, the analysis of previously described DUOX2 mutated cases confirmed the validity of these findings. CONCLUSIONS: The defects in the peroxide generation system are common among congenital hypothyroidism patients with PIOD. The most robust clinical parameters for selecting patients for DUOX2 analysis have been identified, and several DUOX2 variants have been functionally characterized.
Authors: Ingrid Jurickova; Erin Bonkowski; Elizabeth Angerman; Elizabeth Novak; Alex Huron; Grayce Akers; Kentaro Iwasawa; Tzipi Braun; Rotem Hadar; Maria Hooker; Sarah Han; David J Cutler; David T Okou; Subra Kugathasan; Anil Jegga; James Wells; Takanori Takebe; Kevin P Mollen; Yael Haberman; Lee A Denson Journal: Inflamm Bowel Dis Date: 2022-07-01 Impact factor: 7.290
Authors: Maricel F Molina; Patricia Papendieck; Gabriela Sobrero; Viviana A Balbi; Fiorella S Belforte; Elena Bueno Martínez; Ezequiela Adrover; María C Olcese; Ana Chiesa; Mirta B Miras; Verónica G González; Mauricio Gomes Pio; Rogelio González-Sarmiento; Héctor M Targovnik; Carina M Rivolta Journal: Endocrine Date: 2022-05-04 Impact factor: 3.925
Authors: Patti Hayes; Sandeep Dhillon; Kim O'Neill; Cornelia Thoeni; Ken Y Hui; Abdul Elkadri; Conghui H Guo; Lidija Kovacic; Gabriella Aviello; Luis A Alvarez; Anne M Griffiths; Scott B Snapper; Steven R Brant; James H Doroshow; Mark S Silverberg; Inga Peter; Dermot P B McGovern; Judy Cho; John H Brumell; Holm H Uhlig; Billy Bourke; Aleixo A Muise; Ulla G Knaus Journal: Cell Mol Gastroenterol Hepatol Date: 2015-09-01
Authors: Adeline K Nicholas; Eva G Serra; Hakan Cangul; Saif Alyaarubi; Irfan Ullah; Erik Schoenmakers; Asma Deeb; Abdelhadi M Habeb; Mohammad Almaghamsi; Catherine Peters; Nisha Nathwani; Zehra Aycan; Halil Saglam; Ece Bober; Mehul Dattani; Savitha Shenoy; Philip G Murray; Amir Babiker; Ruben Willemsen; Ajay Thankamony; Greta Lyons; Rachael Irwin; Raja Padidela; Kavitha Tharian; Justin H Davies; Vijith Puthi; Soo-Mi Park; Ahmed F Massoud; John W Gregory; Assunta Albanese; Evelien Pease-Gevers; Howard Martin; Kim Brugger; Eamonn R Maher; V Krishna K Chatterjee; Carl A Anderson; Nadia Schoenmakers Journal: J Clin Endocrinol Metab Date: 2016-08-15 Impact factor: 5.958