Molecular diagnosis of rare thyroid pathologies.

MOLINA, MARICEL F.; ADROVER, EZEQUIELA; GONZÁLEZ-SARMIENTO, ROGELIO; TARGOVNIK, HÉCTOR M.; RIVOLTA, CARINA M.

Mar del Plata

Congreso; LXIV Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica.; 2019

Sociedad Argentina de Investigación Clínica

Resistance to thyroid hormone (RTH) is a rare syndrome, with decreased sensitivity to thyroid hormone which leads to elevated serum TH concentrations, but inappropriately normal or elevated thyroid stimulating hormone concentrations. This disease is mostly caused by mutations of thyroid hormone receptor beta (THRB) gene. The incidence is estimated to be 1 in 40,000-50,000. Thyroxine-binding globulin (TBG) is the main transporter of thyroid hormones and is encoded by the TBG gene. Several mutations have been reported in TBG gene causing partial TBG deficiency (TBG-PD) whose prevalence is 1:4000. Molecular diagnosis has been carried out in 34 and 16 unrelated argentinian families with clinical evidences of RTH and TBG-DP respectively. Genomic DNA was isolated from blood cells and the exons 7-10 of the THRB gene and exons 0-5 of TBG gene were amplified by PCR and sequenced by Sanger technique. The novel missense mutations identified were analyzed by in silico studies to elucidate a correlation between structural disturbances and putative functional commitment. 26 mutations in THRB have been identified; 11 novel mutations: p.K306T, p.D351E, p.N331D, p.L341P, p.L346F, p.I431M, p.P447T, p.P453L, p.A335P, c.1276_1277insTGA (p.V425_T426insM) and p.A433CfsX28 and 15 previously reported mutaciones: p.I250T, p.A268G, p.A317T, p.R320H, p.N332R, p.R338W, p.G345R, p.H435P, p.R438H, p.K443N, p.P452L, p.P453T, p.P453L, p.F459C, p.F459L, p.E460K. The more frequent mutations are p.P453T, p.R338E, p.A268G and p.R320H identified in 5, 3,2 and 2 families respectively. 10 mutations in TBG gene have been identified; 9 novel mutations: g.IVS1+2delT, g.IVS1+6T>C, p.A64D, p.N154Y, p.A188T, p.L237R, p.Y241X, p.Q256X , p.A333S and a known mutation: p.T38TfsX13. g.IVS1+2delT , g.IVS1+6T>C and p.A188T are present in 5, 2 and 2 families respectively.This work contributes to elucidate the molecular basis of RTH and TBG-PD and the improvement of the diagnosis avoiding unnecessary therapy and side effects.