TARGOVNIK Hector Manuel
congresos y reuniones científicas
Identification and molecular characterization of four novel mutations in the thyroid hormone receptor beta gene responsible for resistance to thyroid hormone.
OLCESE, MARÍA C; ADROVER, EZEQUIELA; AGUINAGA, AGUSTINA; DIAS, VERA M. A.; CHIESA, ANA; MIRAS, MIRTA B; BRACAMONTE, ROCIO; MÓNICA BRE; TARGOVNIK , HÉCTOR M; RIVOLTA CARINA M
Mar del PLata
Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2016
Sociedad Argentina de Investigación Clínica
Resistance to thyroid hormone (RTH), usually due to heterozygous mutations in thyroid hormone receptor beta (RTbeta) gene, is characterized by raised T4 and T3 levels, nonsuppressed TSH, and a variable phenotype encompassing both hyperthyroid and hypothyroid features. Since 1969 when RTH was first reported, more than 3000 cases and over 125 mutations have been identified. The incidence is estimated to be 1 in 40,000. 6 unrelated argentinian families with clinical evidences of RTH were studied. In order to identify mutations causing this pathology, genomic DNA was isolated from blood cells and the exons 7-10 of the TRbeta gene, including the flanking intronic regions were amplified by PCR. DNA sequences from each amplified fragment were performed with the Taq polymerase-based chain terminator method and using the specific forward and reverse TRbeta primers. Direct sequence analysis revealed 2 novel missense mutations in exón 9: c.917A>C transvertion that results in a p.K306T substitution and c.1012C>G transition causing a p.R336L change and two known missense mutations: c.959G>A; p.R320H and c.1378G>A; p.E460K. A novel mutation in exon 10: c.1304A>C transvertion that results in a p.H435P substitution was identified too. In silico studies were performed to elucidate a correlation between structural disturbances and putative functional commitment, achievinga possible explanation of the pathogenic mechanism of the novel missense mutations analysed. All new substitutions are located in positions evolutionarily conserved and modify the structure of the TRbeta. Due to errors in diagnosis, patients may be inappropriately treated with anti-thyroid drugs for a long period of time or suffer thyroid ablation. Molecular analysis is essential for the diagnosis and treatment of this patients group as well as to increase our understanding of the pathophysiology of the thyroid gland.