MOLECULAR DIAGNOSIS OF RARE THYROID PATHOLOGIES.

MARICEL MOLINA; EZEQUIELA ADROVER

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

Resistance to thyroid hormone (RTH) is arare syndrome, with decreased sensitivity to thyroid hormonewhich leads to elevated serum TH concentrations, butinappropriately normal or elevated thyroid stimulating hormoneconcentrations. This disease is mostly caused by mutations ofthyroid hormone receptor beta (THRB) gene. The incidence isestimated to be 1 in 40,000-50,000. Thyroxine-binding globulin(TBG) is the main transporter of thyroid hormones and isencoded by the TBG gene. Several mutations have been reportedin TBG gene causing partial TBG deficiency (TBG-PD) whoseprevalence is 1:4000. Molecular diagnosis has been carried out in34 and 16 unrelated argentinian families with clinical evidencesof RTH and TBG-DP respectively. Genomic DNA was isolated fromblood cells and the exons 7-10 of the THRB gene and exons 0-5of TBG gene were amplified by PCR and sequenced by Sangertechnique. The novel missense mutations identified wereanalyzed by in silico studies to elucidate a correlation betweenstructural disturbances and putative functional commitment. 26mutations in THRB have been identified; 11 novel mutations:p.K306T, p.N331D, p.A335P, p.L341P, p.L346F, p.D351E,c.1276_1277insTGA (p.V425_T426insM), p.I431M,p.A433CfsX28, p.P447T and p.P453L and 15 previously reportedmutations: p.I250T, p.A268G, p.A317T, p.R320H, p.G332R,p.R338W, p.G345R, p.H435P, p.R438H, p.K443N, p.P452L,p.P453T, p.F459C, p.F459L, p.E460K. The more frequentmutations are p.P453T, p.R338W, p.A268G and p.R320Hidentified in 5, 3, 2 and 2 families respectively. 10 mutations inTBG 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 arepresent in 5, 2 and 2 families respectively. This work contributesto elucidate the molecular basis of RTH and TBG-PD and theimprovement of the diagnosis avoiding unnecessary therapy andside effects.