The role of selenoproteins in thyroid hormone development.
The selenoproteins specifically examined were deiodinases (DIOs) which catalyze the conversion of T4 to T3. Individuals of a Bedouin Saudi family were studied who had been tested for abnormal thyroid function. These individual exhibited symptoms of abnormal thyroid function such as short stature, delayed bone age, and delayed puberty.
In addition, they had high levels of TSH, high levels of T4, but low levels of T3. It was hypothesized that the abnormal hormone levels were due to a defect in the DIO portion protien. To test this hypothesis, the affected individuals were given levothyroxine (L-T4) and liothyronine (L-T3) and measured for negative feedback to reduce TSH levels. It was found that, when compared against unaffected individuals from the same family, higher levels of L-T4 were required to induce negative feedback where as high levels of T3 were not. These results indicate that it is a defect in the conversion of T4 to T3 that results in the abnormal hormone levels. To further confirm this, DIO2 function was tested in vitro in fibroblasts; when stimulated with cAMP, DIO2 mRNA increased in both affected and unaffected individuals, but DIO2 enzymatic activity only increased in unaffected individuals. From this data it was suggested that there is a post-transcriptional defect in DIO2, and with linkage analysis it was determined that the affected individuals were homozygous for a missense mutation not in the DIO2 gene, but in the selenocystiene (Sec) incorporation binding protein (SECISBP) gene. Sec incorporation is essential in proper DIO2 activity; therefore, impairment of SECISBP leads to impaired DIO2 function. A second family was also identified in which heterozygous individuals for a SECISBP mutation exhibited abnormal thyroid hormone levels. In these affected individuals a different mutation was found resulting in improper splicing and early protein truncation of SECISBP. Finally, because SECISBP affects other selenoproteins in addition to DIO2, the activity levels of GPx and the serum levels of selenoprotein P (SePP) were examined using fibroblasts of affected and unaffected individuals. It was found that GPx activity levels and SePP serum levels were both lower in fibroblasts from affected individuals. Researchers found it surprising that given the role of SECISBP is Sec incorporation in multiple selenoproteins that phenotypes in affected individuals were so mild; they expected more defects due to abnormalities in other selenoproteins resulting from lack of Sec incorporation.
This study was limited in its ability to test all forms of DIO (1, 2, and 3) because DIO1 and DIO 3 were not found in fibroblasts, and therefore could not be studies in vitro. DIO 1 and DIO 2 both convert T4 to active T3 and DIO3 converts T4 to reverse T3 which cannot bind to the T3 receptors. A follow up study could be to examine the role of DIO1 and DIO3 in thyroid hormone metabolism in isolation. To look at DIO1, knock-out mice for DIO2 and DIO3 could be created to test if, given high enough T4 levels, is DIO1 sufficient to convert T4 to active T3? Knock-out mice for DIO1 and DIO2 mice could also be created to examine DIO3 to determine if there is any function of reverse T3, at high enough levels. Also, I think it would be interesting to look at the genetic family history of both families to see if one could determine when the mutations occurred.
Alexander Krzyston S Alexander J Krzyston S Alex James Krzyston
Alex Krzyston S Alex J Krzyston S Alexander James Krzyston
NORTHWESTERN UNIVERSITY S EVANSTON S BURR RIDGE
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