Molecular diagnosis of rare thyroid pathologies.

MARICEL F. MOLINA; EZEQUIELA ADROVER; HÉCTOR M. TARGOVNIK; CARINA M. RIVOLTA; ROGELIO GONZALEZ SARMIENTO

Mar del Plata

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

Sociedad Argentina de Investigación Clínica.

Resistance to thyroid hormone (RTH) is a rare syndrome, with decreasedsensitivity to thyroid hormone which leads to elevated serum TH concentrations,but inappropriately normal or elevated thyroid stimulating hormoneconcentrations. This disease is mostly caused by mutations of thyroid hormonereceptor beta (THRB) gene. The incidence is estimated to be 1 in40,000-50,000. Thyroxine-binding globulin(TBG) is the main transporter of thyroid hormones and is encoded by the TBGgene. Several mutations have been reported in TBG gene causing partial TBGdeficiency (TBG-PD) whose prevalence is 1:4000. Molecular diagnosis has beencarried out in 34 and 16 unrelated argentinian families with clinicalevidences of RTH and TBG-DP respectively. Genomic DNA was isolated from bloodcells and the exons 7-10 of the THRB gene and exons 0-5 of TBG gene wereamplified by PCR and sequenced by Sanger technique. The novel missensemutations identified were analyzed by in silico studies to elucidate acorrelation between structural disturbances and putative functional commitment.26 mutations 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 15previously reported mutations: 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 frequent mutations are p.P453T, p.R338W, p.A268G andp.R320H identified in 5, 3, 2 and 2 families respectively. 10  mutations in TBG gene have been identified; 9novel 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 presentin 5, 2 and 2 families respectively.This work contributes to elucidate the molecularbasis of RTH and TBG-PD and the improvement of the diagnosis avoidingunnecessary therapy and side effects.