IDENTIFICATION AND MOLECULAR CHARACTERIZATION OF FOUR NOVEL MUTATIONS IN THE THYROID HORMONE RECEPTOR BETA GENE RESPONSIBLE FOR RESISTANCE TO THYROID HORMONE

MARÍA CECILIA OLCESE; ADROVER E; MOLINA MF

Mar del Plata

Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2016

SAIC

Resistance to thyroid hormone (RTH), usually due to heterozygous mutations in thyroid hormone receptor beta (TRbeta) 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. 4 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 TRbeta forward and reverse primers. Direct sequence analysis revealed 3 novel missense mutations in exon 9: c.917A>C transvertion that results in a p.K306T substitution; c.959G>A transition results in a p.R320H and c.1012C>G transition causing a p.R338W change. And one novel mutation in exon 10: c.1304A>C transvertion that results in a p.H435P substitution. In silico studies were performed to elucidate a correlation between structural disturbances and putative functional commitment, achieving a possible explanation of the pathogenic mechanism of the novel missense mutations analysed. All 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. There is a need to characterize this group of patients.