Browsing by keyword "Hyperthyroidism"
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A novel activating mutation in transmembrane helix 6 of the thyrotropin receptor as cause of hereditary nonautoimmune hyperthyroidismConstitutively-activating germline mutations of the thyrotropin receptor (TSHR) gene are very rare and are considered the cause of hereditary nonautoimmune hyperthyroidism. We describe four affected individuals from a Caucasian family: a mother and her three children, and an unaffected father. The mother and her first two children presented in a similar manner: lifelong histories of heat intolerance, hyperactivity, fast heart rate, reduced energy, increased appetite, and scrawny build. They all developed goiter in childhood and showed a suppressed TSH and elevated thyroxine (T(4)). The last child, a 12-year-old female, presented with no clinical symptoms or palpable neck mass, but with a suppressed TSH, elevated T(4) and thyromegaly detected by ultrasound. Mutation analysis of the TSHR gene in all family members revealed a novel heterozygous germline mutation resulting in the substitution of phenylalanine (TTC) by serine (TCC) at codon 631 in transmembrane helix 6 in the mother and all three children. Functional characterization of this germline mutation showed constitutive activation of the G(s)-mediated cyclic adenosine monophosphate (cAMP) pathway, which controls thyroid hormone production and thyroid growth. Molecular characterization of F631S demonstrates that this activating mutation plays a key role in the development of hereditary hyperthyroidism in this family although the timing of onset of clinical manifestations in the subjects may depend on other, as yet unidentified, factors.
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Affinity labeling of rat liver and kidney type I 5'-deiodinase. Identification of the 27-kDa substrate binding subunitExtrathyroidal production of 3,3',5-triiodothyronine from the thyroid secretory product, thyroxine, is catalyzed by tissue-specific iodothyronine 5'-deiodinases. Type I 5'-deiodinase (5'D-I) produces greater than 75% of the T3 found in the circulation and in thyroid hormone-responsive tissues and is most abundant in rat liver and kidney. In this study, we used the bromoacetyl derivatives of T4 (N-bromoacetyl-[125I]L-thyroxine, BrAcT4) and T3 (N-bromoacetyl-[125I]3,3',5-triiodothyronine, BrAcT3) as alkylating affinity labels to identify 5'D-I-related protein(s). BrAcT4 and BrAcT3 rapidly and irreversibly inactivated 5'D-I activity in liver and kidney microsomes. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of affinity labeled 5'D-I preparations showed that approximately 80% of the affinity label was incorporated into a protein with a Mr of 27,000 (p27). 5'D-I substrates and inhibitors specifically blocked affinity labeling of p27 with a rank order of potency (BrAcT4 greater than BrAcT3 greater than 3,5,3'-triiodothyronine (rT3) approximately flavone EMD 21388 greater than iodoacetate greater than N-acetyl-T4 (NAcT4) greater than N-acetyl-T3 (NAcT3] identical to that determined for inhibition of 5'-deiodination. Hyper- and hypothyroidism-induced increases and decreases in 5'D-I activity, respectively, were matched by comparable changes in the quantity of affinity labeled p27. BrAcT3 was a less effective affinity label for p27 and minor labeling of a new band with 53 kDa was observed. Molecular sieve chromatography of detergent-solubilized 5'D-I showed coincident peaks of p27 and 5'-deiodinating activity with an apparent Mr approximately 51,000. Two-dimensional gel electrophoresis showed that p27 was a single polypeptide with a pI of 6.1. Approximately 2-5 pmol of p27 were present per mg of liver microsomal protein, equal to previous estimates for 5'D-I content. Our results suggest that p27 represents the substrate binding subunit of type I 5'-deiodinase, the enzyme catalyzing the key reaction in the activation of T4 to the thyromimetically active T3.
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Radionuclide thyroid studies: analysis of use and correlation with physical findingsWe assessed all thyroid radionuclide studies done at a single institution during one year and evaluated the indication for ordering each study as well as the concordance of study results with those of physical examination. We found that thyroid radionuclide imaging was overused, with at most 66% of scans being indicated (using the most generous classification of a proposed rating for indications). Radioactive iodine uptake measurement done without scanning was probably underused. Concordance between the results of physical examination and scanning was reflected by an overall agreement rate of 51%; agreement between results of scanning and physical examination beyond what might be expected by chance alone was reflected by a kappa value of .34. Concordance was strongest for diffuse goiters and weakest for normal findings.
