Molecular analysis of thyroglobulin mutations found in patients with goiter and hypothyroidism
| Autor: | Ana Chiesa, Rogelio González-Sarmiento, Héctor M. Targovnik, Patricia Papendieck, Sofia Siffo, Mirta Miras, Viviana Balbi, Elena Bueno Martinez, Verónica González, Cintia E. Citterio, Gabriela Sobrero, Jacques Weill, Ezequiela Adrover, Carina M. Rivolta |
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| Přispěvatelé: | Fondo Nacional de Desarrollo Científico y Tecnológico (Chile), Fondo para la Investigación Científica y Tecnológica (Argentina), Agencia Nacional de Promoción Científica y Tecnológica (Argentina), Ministerio de Ciencia, Tecnología e Innovación Productiva (Argentina), Universidad de Buenos Aires |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment DNA Mutational Analysis Ciencias de la Salud Gene mutation Compound heterozygosity medicine.disease_cause Biochemistry Thyroglobulin gene 0302 clinical medicine Endocrinology Thyroid dyshormonogenesis Gene Frequency Chromosome Segregation Missense mutation Child Mutation Goiter Pedigree Child Preschool purl.org/becyt/ford/3 [https] Female CIENCIAS MÉDICAS Y DE LA SALUD Adolescent 030209 endocrinology & metabolism Biology Thyroglobulin 03 medical and health sciences purl.org/becyt/ford/3.3 [https] Hypothyroidism medicine Congenital Hypothyroidism Humans Family Genetic Predisposition to Disease Amino Acid Sequence Allele Molecular Biology Salud Ocupacional Base Sequence Genetic heterogeneity Truncated thyroglobulin protein Infant Newborn medicine.disease Molecular biology 030104 developmental biology Haplotypes |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET Digital.CSIC: Repositorio Institucional del CSIC Consejo Superior de Investigaciones Científicas (CSIC) |
| Popis: | Thyroid dyshormonogenesis due to thyroglobulin (TG) gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism. Up to now, one hundred seventeen deleterious mutations in the TG gene have been identified and characterized. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report eight patients from seven unrelated families with goiter, hypothyroidism and low levels of serum TG. All patients underwent clinical, biochemical and image evaluation. Sequencing of DNA, genotyping, as well as bioinformatics analysis were performed. Molecular analyses revealed three novel inactivating TG mutations: c.5560G>T [p.E1835*], c.7084G>C [p.A2343P] and c.7093T>C [p.W2346R], and four previously reported mutations: c.378C>A [p.Y107*], c.886C>T [p.R277*], c.1351C>T [p.R432*] and c.7007G>A [p.R2317Q]. Two patients carried homozygous mutations (p.R277*/p.R277*, p.W2346R/p.W2346R), four were compound heterozygous mutations (p.Y107*/p.R277* (two unrelated patients), p.R432*/p.A2343P, p.Y107*/p.R2317Q) and two siblings from another family had a single p.E1835* mutated allele. Additionally, we include the analysis of 48 patients from 31 unrelated families with TG mutations identified in our present and previous studies. Our observation shows that mutations in both TG alleles were found in 27 families (9 as homozygote and 18 as heterozygote compound), whereas in the remaining four families only one mutated allele was detected. The majority of the detected mutations occur in exons 4, 7, 38 and 40. 28 different mutations were identified, 33 of the 96 TG alleles encoded the change p.R277*. In conclusion, our results confirm the genetic heterogeneity of TG defects and the pathophysiological importance of the predicted TG misfolding and therefore thyroid hormone formation as a consequence of truncated TG proteins and/or missense mutations located within its ACHE-like domain. This study was funded by grants from the FONCyT-ANPCyT-MINCyT (PICT 2014-1193 to CMR, PICT 2012-1090 and PICT 2015–1811 to HMT), CONICET (PIP 2015-11220150100499 to CMR) and Universidad de Buenos Aires (UBACyT 2016-20020150100099BA to CMR). |
| Databáze: | OpenAIRE |
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