Hormonas Tiroideas y Cerebro. Notas Sobre La Relación Bocio y ...

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composition of this enzyme system are recent (5, 6). Among the two recently cloned NADPH oxidases, THOX1 and THOX2 (also referred to as DUOX1 and DUOX2), THOX2 is essential for thyroidal H 2 O 2 generation. Structurally, these proteins contain seven putative transmembrane domains, four NADPH binding sites, one FAD binding site, and in line with the predicted regulation by calcium an EF (everted finger) motif (5, 6). Heterozygous loss of function mutations in the THOX2 gene result in mild transient congenital hypothyroidism (22). Biallelic THOX2 mutations are associated with a severe phenotype and confirm that H 2 O 2 is essential for iodide organification (22). THOX2 (DUOX2) requires a maturation factor, DUOXA2, an ER-resident transmembrane protein, in order to translocate to the cell membrane (23). Mutations in DUOX2 result in impaired trafficking to the cell membrane (24). Thyroglobulin Thyroglobulin (TG) is produced by thyroid follicular cells and secreted into the follicular lumen (7). Some of its tyrosine residues are iodinated by TPO (organification/iodination), and the tyrosines MIT and DIT are subsequently coupled to form T3 and T4 (coupling). TG is therefore considered to be a thyroid hormone precursor. Besides its importance for hormone synthesis, TG allows storage of iodine and thyroid hormone and thus to adapt to scarce iodine supply. The human TG gene is very large, spans about 270 kb and contains 48 exons. The transcription of the TG gene is controlled by transcription factors such as TTF-1 (NKX2.1), TTF-2 (FOXE1) and PAX 8. The TG protein monomer is composed of a 19-amino acid signal peptide followed by 2749 residues containing 66 tyrosines. TG contains an average number of tyrosine residues, altogether 67, but only a minority of these residues localized in the carboxy- and aminoterminus are hormonogenic sites. Complete hydrolysis of iodinated TG yields only 2 to 4 molecules of the iodothyroxines T4 and T3. The mature protein is formed by two units in noncovalent linkage (19 S TG). 10 % of the total weight is formed by carbohydrates and glycosylation plays an important role in the structure of the protein. The primary structure of the TG protein contains three regions with repetitive sequences with internal homology and the carboxy-terminal part shares remarkable homology with acetylcholinesterase. This structure suggests the possibility of a convergent origin of the TG gene from two different ancestral DNA sequences (7). Defects of TG synthesis or secretion have been studied in several animal strains and human patients (25). TG gene defects are inherited in an autosomal recessive manner. The phenotype is typically characterized by goitrous enlargement of the thyroid. The metabolic status is variable and, depending on the severity of the defect, the patients are hypothyroid, subclinically hypothyroid, or euthyroid. Unless treated with levothyroxine, goiters are often remarkably large and display continuous growth. Symptoms caused by compression of adjacent neck structures can occur. The radioiodine uptake is elevated indicating an activation of the iodine concentration mechanism, due to chronic stimulation of TSH. In patients evaluated with a perchlorate discharge test, there is no increased release of radioiodine after administration of the competitor, indicating that the organification process itself is not affected. The serum TG levels can vary from low to low normal, and the presence of an abnormal TG level in a goitrous individual is suggestive for defective TG synthesis. An abnormal TG synthesis may also be suggested by the presence of abnormal iodoproteins in the serum. Since there is no normal intrathyroidal TG, albumin as well as other proteins are iodinated, generating iodotyrosines and iodohistidines. Molecular analysis of several TG point mutations found in patients with congenital hypothyroidism and in the cog/cog mouse, which all present with goiters, reveal that at least some of these alterations result in a secretory defect and thus an endoplasmic reticulum storage disease (ERSD) (26, 27). 10
It has been proposed that TG mutations may be associated with non-endemic simple goiter. These results await, however, further confirmation; the TG gene contains multiple polymorphisms, and in the absence of functional data it remains unclear whether these reported alterations are indeed causally involved in the abnormal phenotype. Dehalogenase 1 defects After entering the follicular cell, TG is hydrolyzed and T4 and T3 are secreted into the blood (Figure 1). The iodotyrosines, MIT and DIT, which are much more abundant in the TG molecule, are deiodinated by the intrathyroidal dehalogenase 1 (DEHAL1) and recycled for hormone synthesis. The intrathyroidal dehalogenase has been cloned recently (8). In case of a defective dehalogenase system, MIT and DIT leak into the circulation and are excreted in the urine. This leads, especially if iodine is scarce, to a severe iodine-loss and thus to hypothyroidism and goiter. Clinically, patients with a deiodinase defect present with congenital hypothyroidism and a goitrous gland. The diagnosis is established by administration of radiolabeled DIT. Normally, DIT is deiodinated, whereas in the case of a defective dehalogenase, the majority is secreted unaltered as DIT in the urine. Furthermore, administration of iodide in sufficient amounts to compensate for the increased loss is able to reestablish an euthyroid metabolic state. The disorder is inherited in an autosomal recessive fashion. While only homozygotes are clinically affected, biochemical testing in heterozygotes demonstrates an increased secretion of labeled DIT in the urine. The clinical and biochemical phenotype of several kindreds have been studied (28), but definitive demonstration of DEHAL1 mutations is currently pending. Acknowledgments The work of the authors has been supported by grant 1R01DK63024-01 from the National Institutes of Health (to PK). References 1. Taurog A 2000 Hormone synthesis: thyroid iodine metabolism. In: Braverman L, Utiger R (eds) Werner and Ingbar's the thyroid: a fundamental and clinical text. Lippincott, Williams & Wilkins, Philadelphia, 61-85. 2. Kopp P 2005 Thyroid hormone synthesis: thyroid iodine metabolism. In: Braverman L, Utiger R (eds) Werner and Ingbar's the thyroid: a fundamental and clinical text. Lippincott, Williams & Wilkins, Philadelphia, 52-76. 3. Dohan O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, Ginter CS, et al. 2003 The sodium/iodide symporter (NIS): characterization, regulation, and medical significance Endocr Rev 24:48-77. 4. Gillam MP, Sidhaye A, Lee EJ, Rutishauser J, Waeber Stephan C, Kopp P 2004 Functional characterization of pendrin in a polarized cell system: evidence for pendrin-mediated apical iodide efflux J Biol Chem 279:13004– 13010. 5. De Deken X, Wang D, Many MC, Costagliola S, Libert F, Vassart G, Dumont JE, et al. 2000 Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family J Biol Chem 275:23227-23233. 6. De Deken X, Wang D, Dumont JE, Miot F 2002 Characterization of ThOX proteins as components of the thyroid H 2 O 2 -generating system Exp Cell Res 273:187-96. 7. Dunn JT, Dunn AD 2000 Thyroglobulin: chemistry, biosynthesis, and proteolysis. In: Braverman LE, Utiger RD (eds) Werner & Ingbar's The thyroid: a fundamental and clinical text. Lippincott Williams & Wilkins, Philadelphia, 91-104. 8. Moreno JC 2003 Identification of novel genes involved in congenital hypothyroidism using serial analysis of gene expression Horm Res 60:96-102. 9. Wolff J, Chaikoff I, Goldberg R, Meier J 1949 The temporary nature of the inhibitory action of excess iodide on organic iodide synthesis in the normal thyroid Endocrinology 45:504-513. 10. De Felice M, Di <strong>La</strong>uro R 2004 Thyroid development and its disorders: genetics and molecular mechanisms Endocr Rev 25:722-46. 11
Page 1 and 2: Hormonas Tiroideas y Cerebro. Notas
Page 3 and 4: Uno de los libros más importantes
Page 5 and 6: ocio (struma). Las observaciones de
Page 7 and 8: Thyroid hormone synthesis Peter Kop
Page 9: eferred to as microsomal antigen in
Page 13 and 14: Thyroid Hormone Transporters Theo J
Page 15 and 16: References 1. Bianco AC, Kim BW 200
Page 17 and 18: T 4 T 3 I HO- I I I HO- -O- -R I I
Page 19 and 20: 1 of every 2 molecules of T 4 . Thu
Page 21 and 22: The Type 3 Deiodinase (D3) and the
Page 23 and 24: parental origin (16). Thus, using t
Page 25 and 26: Action of Thyroid Hormone in Brain
Page 27 and 28: Hormonas Tiroideas y Migración Neu
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Page 31 and 32: Función fetal y materna. Un panora
Page 33 and 34: Nacer EDAD GESTACIONAL (semanas) ED
Page 35 and 36: Este fenómeno ha sido observado in
Page 37 and 38: 14. Ausó E, Lavado.Autric R, Cueva
Page 39 and 40: solicita un perfil tiroideo complet
Page 41 and 42: Referencias. 1. Money J, Clarke FC,
Page 43 and 44: • Concentraciones de T4: lograr c
Page 45 and 46: 9. Fisher DA. 2000 The importance o
Page 47 and 48: starting dosage are ever fully norm
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