Dumitrescu, Alexandra M.; Refetoff, S.
April 2007
Acta Endocrinologica (1841-0987);Apr-Jun2007, Vol. 3 Issue 2, p189
Academic Journal
Intracellular metabolism of thyroid hormone (TH) and availability of the active hormone T3 is regulated by three selenoprotein iodothyronine deiodinases (Ds). D1 and D2 convert the precursor T4 into the active hormone, T3. D3 is the principal inactivator of T4 and T3 to their respective metabolites, rT3 and T2. While acquired changes in D activities are common, inherited defects in humans were not known. Recently, we identified two families with abnormal thyroid function tests: high serum T4, high rT3, low T3 and slightly increased TSH. Linkage analysis and sequencing excluded abnormalities in all 3 deiodinase genes, yet clinical studies showed reduced responsiveness to T4 but not to T3. Extensive search for putative defects in genes encoding proteins involved in the synthesis of the active D2 selenoenzyme and in its degradation by ubiquitination, led to the identification of mutations in the selenocysteine insertion sequence binding protein (SBP)2 gene, involved in the synthesis of selenoproteins, including the deiodinases. Affected children were either homozygous or compound heterozygous for SBP2 mutations. Other selenoproteins, including glutathione peroxidase and selenoprotein P were also reduced in affected subjects, confirming a generalized effect of the SBP2 defect. Insight into the consequences of SBP2 defect is novel and represents an interesting example of an epistatic effect resulting in deficiency of selenoproteins.


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