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Molecular diagnosis of Partial Thyroxine-binding Globulin Defiency: A contribution to translational medicine
MOLINA MF; ADROVER E
Congreso; Reunión conjunta de Sociedades de Biociencias; 2017
Thyroxine-binding globulin (TBG) is the main transporter of thyroid hormones in serum. TBG gene is located on the X-chromosome (Xq21-q22) and contains 4 coding exons spanning 7.5 kb in the genome. TBG defects lead to three phenotypes according to serum TBG concentrations, complete TBG deficiency (TBG-CD), partial TBG deficiency (TBG-PD) and TBG excess (TBG-E). Women with homozygous inactivating mutations and men hemizygous for a deleterious mutation usually manifest as TBG-CD, and heterozygous women as TBG-PD. Gen duplication or triplications have been associated with TBG-E. 45 distinct mutations have been identified and characterized in the human TBG. Prevalence of TBG-PD is 1:4000.Three unrelated Argentinean families with clinical-biochemical diagnosis of TBG-PD were analyzed. In order to identify mutations causing this pathology, genomic DNA was isolated from blood cells and the exons 0-5 of the TBG 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 TBG forward and reverse primers. Direct sequence analysis revealed 3 novel mutations, two nonsense mutations and a missense mutation. Patient 1 showed an hemizygous mutation in exon 2: c.826C>T transition that results in a p.Q276* substitution which was inherited from his mother. Patient 2 carries an hemizygous c.783C>A transvertion in exon 2 which results in a p.Y261* and was inherited from his mother. Patient 3 showed a c.622G>A transition; p.A208T in exon 1. 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 mutation identified. This work contributes to elucidate the molecular basis of the defects of thyroid hormone transport in serum and the improvement of the diagnosis avoiding unnecessary therapy.