Maricel F Molina1,2, Patricia Papendieck3, Gabriela Sobrero4, Viviana A Balbi5, Fiorella S Belforte1,2, Elena Bueno Martínez6, Ezequiela Adrover1,2, María C Olcese1,2, Ana Chiesa3, Mirta B Miras4, Verónica G González5, Mauricio Gomes Pio1,2, Rogelio González-Sarmiento6, Héctor M Targovnik1,2, Carina M Rivolta7,8. 1. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología, Biotecnología y Genética/Cátedra de Genética, Universidad de Buenos Aires, Buenos Aires, Argentina. 2. Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina. 3. Centro de Investigaciones Endocrinológicas, CEDIE-CONICET, División Endocrinología, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina. 4. Servicio de Endocrinología, Hospital de Niños Santísima Trinidad, Córdoba, Argentina. 5. Servicio de Endocrinología, Hospital de Niños "Sor María Ludovica", La Plata, Argentina. 6. Unidad de Medicina Molecular-Departamento de Medicina, IBMCC and IBSAL, Universidad de Salamanca-CSIC, Salamanca, España. 7. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología, Biotecnología y Genética/Cátedra de Genética, Universidad de Buenos Aires, Buenos Aires, Argentina. crivolta@ffyb.uba.ar. 8. Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina. crivolta@ffyb.uba.ar.
Abstract
PURPOSE: Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 17 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH). METHODS: Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO), Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), DUOX2, Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants. RESULTS: Four novel variants have been identified, two in TPO: c.2749-2 A > C and c.2752_2753delAG, [p.Ser918Cysfs*62] and two variants in DUOX2 gene: c.425 C > G [p.Pro142Arg] and c.2695delC [p.Gln899Serfs*21]. Eighteen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic biallelic variants in TPO and DUOX2 in 7 and 2 patients, respectively. We also detected a potentially pathogenic monoallelic variant in TPO and DUOX2 in 7 and 1 patients respectively. CONCLUSIONS: 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.
PURPOSE: Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 17 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH). METHODS: Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO), Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), DUOX2, Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants. RESULTS: Four novel variants have been identified, two in TPO: c.2749-2 A > C and c.2752_2753delAG, [p.Ser918Cysfs*62] and two variants in DUOX2 gene: c.425 C > G [p.Pro142Arg] and c.2695delC [p.Gln899Serfs*21]. Eighteen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic biallelic variants in TPO and DUOX2 in 7 and 2 patients, respectively. We also detected a potentially pathogenic monoallelic variant in TPO and DUOX2 in 7 and 1 patients respectively. CONCLUSIONS: 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.
Authors: Fiorella S Belforte; Alexandra M Targovnik; Rodolfo M González-Lebrero; Carolina Osorio Larroche; Cintia E Citterio; Rogelio González-Sarmiento; María V Miranda; Héctor M Targovnik; Carina M Rivolta Journal: Mol Cell Endocrinol Date: 2015-01-07 Impact factor: 4.102
Authors: Carina M Rivolta; Sebastián A Esperante; Laura Gruñeiro-Papendieck; Ana Chiesa; Christian M Moya; Sabina Domené; Viviana Varela; Héctor M Targovnik Journal: Hum Mutat Date: 2003-09 Impact factor: 4.878
Authors: José C Moreno; Hennie Bikker; Marlies J E Kempers; A S Paul van Trotsenburg; Frank Baas; Jan J M de Vijlder; Thomas Vulsma; C Ris-Stalpers Journal: N Engl J Med Date: 2002-07-11 Impact factor: 91.245
Authors: Sue Richards; Nazneen Aziz; Sherri Bale; David Bick; Soma Das; Julie Gastier-Foster; Wayne W Grody; Madhuri Hegde; Elaine Lyon; Elaine Spector; Karl Voelkerding; Heidi L Rehm Journal: Genet Med Date: 2015-03-05 Impact factor: 8.822