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

MARÍA CECILIA OLCESE; EZEQUIELA ADROVER; CARINA M RIVOLTA

Congreso; LXI reunión científica anual de la sociedad de investigación clínica; 2016

SAIC

Resistance to thyroid hormone (RTH), usually due to heterozygousmutations in thyroid hormone receptor beta (TRbeta) gene, is characterized byraised T4 and T3 levels, nonsuppressed TSH, and a variable phenotypeencompassing both hyperthyroid and hypothyroid features. Since 1969 when RTHwas first reported, more than 3000 cases and over 125 mutations have beenidentified. The incidence is estimated to be 1 in 40,000. 6 unrelatedargentinian families with clinical evidences of RTH were studied. In order toidentify mutations causing this pathology, genomic DNA was isolated from bloodcells and the exons 7-10 of the TRbeta gene, including the flanking intronicregions were amplified by PCR. DNA sequences from each amplified fragment wereperformed with the Taq polymerase-based chain terminator method and using thespecific forward and reverse TRbeta primers. Direct sequence analysis revealed2 novel missense mutations in exon 9: c.917A>C transvertion that results in a p.K306T substitution andc.1012C>G transition causing a p.R338L change and two known missensemutations: c.959G>A; p.R320H and c.1378G>A; p.E460K. A novel mutation inexon 10: c.1304A>C transvertion that results in a p.H435P substitution wasidentified too. In silico studies were performed to elucidate a correlationbetween structural disturbances and putative functional commitment, achieving apossible explanation of the pathogenic mechanism of the novel missense mutationsanalysed. All new substitutions are located in positions evolutionarilyconserved and modify the structure of the TRbeta. Due to errors in diagnosis,patients may be inappropriately treated with anti-thyroid drugs for a longperiod of time or suffer thyroid ablation. Molecular analysis is essential forthe diagnosis and treatment of this patients group as well as to increase ourunderstanding of the pathophysiology of the thyroid gland.