References

ketendo

Клиническая и экспериментальная тиреоидология

Clinical and experimental thyroidology

1995-54722310-3787

Endocrinology Research Centre

10.14341/ket2005114-16

ketendo-4307

Research Article

Статьи

Articles

ГЕНЫ-КАНДИДАТЫ ТИРЕОИДНОЙ ПАТОЛОГИИ

Candidate Genes in thyroid disorders

Troshina

Masurina

Galkina

2005

15032005

ТОМ 1, №1 (2005)

416

2005

Troshina E., Masurina N., Galkina N.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.cet-endojournals.ru/jour/article/view/4307

Этиология и патогенез большинства заболеваний, протекающих как с гипотиреозом, так и с тиреотоксикозом, в настоящее время достаточно хорошо известны. Основными методами лечения этих заболеваний продолжают оставаться тиреоидэктомия, терапия радиоактивным йодом и тиреостатиками в случае тиреотоксикоза или заместительная терапия препаратами тиреоидных гормонов в случае гипотиреоза. Тем не менее в последние десятилетия приобретает все большее значение генная терапия наследственных заболеваний. В данной статье авторы представляют обзор литературы по вопросам генетических нарушений гормоногенеза тиреоидных гормонов, в которой детально охарактеризованы мутации генов TSHR, NIS, TPO, THOX, TG и клинический фенотип развивающихся при них заболеваний. При этом показано, что идентичные мутации (например, T354P NIS) могут обусловливать формирование различных клинических фенотипов, начиная от эутиреоидного зоба и заканчивая врожденным гипотиреозом: у одних пациентов развивается кретинизм, в то время как у других отсутствуют нарушения функции щитовидной железы и неврологические нарушения. Такая клиническая гетерогенность может быть обусловлена генными взаимодействиями, типом наследования, а также факторами окружающей среды. Эта статья обращает внимание эндокринологов на заболевания щитовидной железы, патогенез которых не связан с йодным дефицитом и патологией иммунной системы.

Hypothyroidism and hyperthyroidism are well known to be the main clinical features of thyroid pathology. Although a lot of mechanisms of these disorders exist, thyroid resection, radioiodine or drug (antithyroid or hormone replacement) therapy are still common treatment methods. However, in the coming century of gene therapy the comprehension of genetic pathways of the diseases may also be very important. In this article authors represent the defects of hormonogenesis in the systems which provide iodine transport and its intrathyrocytes reactions. TSHR, NIS, TPO, THOX, TG are detailed characterized, some mutations of these genes and corresponding clinical syndromes are described. It’s interesting that in some cases the identical mutation (for example T354P NIS) may have marked heterogenity in clinical pictures: from euthyroid goiter to congenital hypothyroidism. Some patients show cretinism and some remain euthyroid without mental or developmental disorders. Gene-gene interaction, inheritance type and environment factors are likely responsible for such clinical polymorphism. The aim of this article was to catch attention of thyroidologist to very important aspect of thyroid pathogenesis which is not connected with iodine deficient or autoimmune diseases. The competence in genetic research area might significant increase the educational level of practitioners. Key words: thyroid, inherited disorders, natrium-iodide simporter, TSH, hypothyroidism, goiter.

References1

Dumont J.E., Lefort A., Libert F. Transducing systems in the control of human thyroid cell function, proliferation, and differentiation. In: Ekholm R., Kohn L.D., Wollman S (eds) Control of the Thyroid: Regulation of its Normal Growth and Function. Plenum Press, New York, 1990. Р. 357-372.

Vassart G., Dumont J.E. The thyrotropin receptor and regulation of thyrocyte function and growth. Endocr Rev. 1992. V. 13. P. 596-611.

Kohn L.D., Shimura H., Shimura Y., Hidaka A., Giuliani C., Napolitano G., Ohmori M., Laglia G., Saji M. The thyrotropin receptor. Vitam Horm.1995. V. 50. P. 287-384.

Nagayama Y., Kaufman K.D., Seto P., Rapoport B. Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor. Biochem. Biophys. Res. Commun. 1989. V. 165. P. 1184-1190.

Paschke R., Ludgate M. The thyrotropin receptor in thyroid diseases. New Eng. J. Med. 1997. V. 337. P. 1675-1681.

Loosfelt, H.; Pichon, C.; Jolivet, A.; Misrahi, M.; Caillou, B.; Jamous, M.; Vannier B., Milgrom E. Two-subunit structure of the human thyrotropin receptor. Proc. Nat. Acad. Sci. 1992. V. 89. P. 3765-3769.

Feliciello A., Porcellini A., Ciullo I. Bonavolonta, G.; Avvedimento, E. V.; Fenzi, G. Expression of thyrotropin-receptor mRNA in healthy and Graves’ disease retro-orbital tissue. Lancet. 1993. V. 342. P. 337-338.

Lazar V., Bidart J.-M., Caillou B., Mahe C., Lacroix L., Filetti S., Schlumberger M. Expression of the Na(+)/I(-) symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J. Clin. Endocr. Metab. 1994. V. 84. P. 3228-3234.

Fuhrer D., Wonerow P., Willgerod H., Paschke R. Identification of a new thyrotropin receptor germline mutation (leu629phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J. Clin. Endocr. Metab. 1997. V. 82. P. 4234-4238.

Parma J., Duprez L., Van Sande J. Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs-alpha genes as a cause of toxic thyroid adenomas. J. Clin. Endocr. Metab. 1997. V. 82. P. 2695-2701.

Krohn K., Wohlgemuth S., Gerber H., Paschke R. Hot microscopic areas of iodine-deficient euthyroid goitres contain constitutively activating TSH receptor mutations. J Pathol. 2000. V. 192(1). P. 37-42.

Hollingsworth D.R., Mabry C.C. Congenital Graves disease: four familial cases with long-term follow-up and perspective. Am. J. Dis. Child. 1976. V. 130. P. 148-155.

Fuhrer D., Wonerow P., Willgerodt H., Paschke R. Identification of a new thyrotropin receptor germline mutation (leu629phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J. Clin. Endocr. Metab. 1997. V. 82. P. 4234-4238.

Kopp P., van Sande J., Parma J., Duprez L., Gerber H., Joss E., Jameson J.L., Dumont J.E., Vassart G. Congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. New Eng. J. Med. 1995. V. 332. P. 150-154.

Sunthornthepvarakul Т., Gottschalk M.E., Hayash, Y. Resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. New Eng. J. Med. 332155-160, 1995

Abramowicz M.J., Duprez L., Parma J. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J. Clin. Invest. , 1997.

Dai G., Levy O., Carrasco N. Cloning and characterization of the thyroid iodide transporter. Nature 379 458-460, 1996.

Smanik P.A., Liu Q., Furminger T.L., Ryu K., Xing S., Mazzaferri E.L., Jhiang S.M. Cloning of the human sodium iodide symporter. Biochem. Biophys. Res. Commun. 226 339-345, 1996.

Halmi N.S., Granner D.K., Doughman D.J., Peters B.H., Muller G. 1959 Biphasic effect of TSH on thyroidal iodide collection in rats. Endocrinology. 1959. V. 67. P. 70-81.

Knopp J., Stolc V., Tong W. Evidence for the induction of iodide transport in bovine thyroid cells treated with thyroid-stimulating hormone or dibutyryl cyclic adenosine 3’-, 5’-monophosphate. J Biol Chem. 1970. V. 245. P. 4403-4408.

Weiss S.J., Philp N.J., Grollman E.F. Iodide transport in a continuous line of cultured cells from rat thyroid. Endocrinology. 1984. V. 114. P. 1090-1098.

Carrasco N. Iodide transport in the thyroid gland. Biochim Biophys Acta. 1993. V. 115. P. 465-482.

Venkataraman G.M., Yatin M., Marcinek R. Restoration of iodide uptake in dedifferentiated thyroid carcinoma: relationship to human Na(+)/I(-) symporter gene methylation status. J. Clin. Endocr. Metab. 1999. V. 84. P. 2449—2457.

Spitzweg C., Joba W., Schriever K. Analysis of human sodium iodide symporter immunoreactivity in human exocrine glands. J. Clin. Endocr. Metab. 1999. V. 84. P. 4178—4184.

Cho J.-Y., Leveille R., Kao R., Rousset B., Parlow A.F., Burak W.E. Jr., Mazzaferri E.L., Jhiang S.M. Hormonal regulation of radioiodide uptake activity and Na+/I- symporter expression in mammary glands. J. Clin. Endocr. Metab. 2000. V. 85. P. 2936—2943.

Fujiwara H., Tatsumi K., Miki K., Harada Т., Miyai K., Takai S., Amino N. Congenital hypothyroidism caused by a mutation in the Na(+)/I(-) symporter. (Letter) Nature Genet. 1997. V. 16. P. 124—125.

Fujiwara H., Tatsumi K.-I., Miki K., Harada Т., Okada S., Nose О., Kodama S., Amino N. Recurrent T354P mutation of the Na+/I-symporter in patients with iodide transport defect. Endocr. Metab. 1998. V. 83. P. 2940—2943.

Matsuda A., Kosugi S. A homozygous missense mutation of the sodium/iodide symporter gene causing iodide transport defect. J. Clin. Endocr. Metab. 1997. V. 82. P. 3966—3971.

Kosugi S., Sato Y., Matsuda A. High prevalence of T354P sodium/iodide symporter gene mutation in Japanese patients with iodide transport defect who have heterogeneous clinical pictures. J. Clin. Endocr. Metab. 1998. V. 83. P. 4123—4129.

Pohlenz J., Rosenthal I.M., Weiss R.E. Congenital hypothyroidism due to mutations in the sodium/iodide symporter: identification of a nonsense mutation producing a downstream cryptic 3-prime splice site. J. Clin. Invest. 1998/ V. 101. P. 1028—1035.

Pohlenz J., Medeiros-Neto G., Gross J.L., Silveiro S.P., Knobel M., Refetoff S. Hypothyroidism in a Brazilian kindred due to iodide trapping defect caused by a homozygous mutation in the sodium/iodide symporter gene. Biochem. Biophys. Res. Commun. 1997. V. 240. P. 488—491.

Couch R.M., Dean H.J., Winter J.S. Congenital hypothyroidism caused by defective iodide transport. J. Pediat. 1985. V. 106. P. 950—953.

Albero R., Cerdan A., Sanchez Franco F. Congenital hypothyroidism from complete iodide transport defect: long-term evolution with iodide treatment. Postgrad. Med. J.1987. V. 63. P. 1043—1047.

Kosugi S., Okamoto H., Tamada A. A novel peculiar mutation in the sodium/iodide symporter gene in Spanish siblings with iodide transport defect. J. Clin. Endocr. Metab. 2002. V. 87. P. 3830—3836.

Kimura S., Kotani Т., McBride O.W. Human thyroid peroxidase: complete cDNA and protein sequence, chromosome mapping, and identification of two alternately spliced mRNAs. Proc. Nat. Acad. Sci. 1987, V. 84. P. 5555—5559.

Haddad H.M., Sidbury J.B. Defect of the iodinating system in congenital goitrous cretinism: report of a case with biochemical studies. J. Clin. Endocr. 1959. V. 19. P. 1446—1457.

Niepomniszcze H., Rosenbloom A.L., Degroot L.J., Shimaoka K., Refetoff S., Yamamoto K. Differentiation of two abnormalities in thyroid peroxidase causing organification defect and goitrous hypothyroidism. Metabolism 1975. V. 24. P. 57—67.

Bikker H., Vulsma Т., Baas F., de Vijlder J.J. M. Identification of five novel inactivating mutations in the human thyroid peroxidase gene by denaturing gradient gel electrophoresis. Hum. Mutat. 1995. V. 6. P. 9—16.

Bakker B., Bikker H., Vulsma Т., De Randamie J.-S. E. Wiedijk B.M., De Vijlder J.J. M. Two decades of screening for congenital hypothyroidism in the Netherlands: TPO gene mutations in total iodide organification defects (an update). J. Clin. Endocr. Metab. 2000. V. 85, P. 3708—3712.

Hagen G.A., Niepomniszcze H., Haibach H., Bigazzi M., Hati R., Rapoport B., Jimenez C., DeGroot L.J., Frawley T.F. Peroxidase deficiency in familial goiter with iodide organification defect. New Eng. J. Med. 1971. V. 285. P. 1394—1398.

Pommier J., Tourniaire J., Deme D., Chalendar D., Bornet H., Nunez J. A defective thyroid peroxidase solubilized from a familial goiter with iodine organification defect. J. Clin. Endocr. 1971. V. 39. P. 69—80.

Perez-Cuvit E., Crigler J.F., Jr. Stanbury J.B. Partial and total iodide organification defect in different sibships in a kindred. Am. J. Hum. Genet. 1977. V. 29. P. 142—148.

Edens W.A., Sharling L., Cheng G. Tyrosine cross-linking of extracellular matrix is catalyzed by Duox, a multidomain oxidase/peroxidase with homology to the phagocyte oxidase subunit gp91phox. J Cell Biol. 2001. V. 154(4). P. 879—891.

Geiszt M., Witta J., Baffi J., Lekstrom K., Leto T.L. Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense. FASEB J. 2003. V. 17(11). P. 1502—1504.

De Deken X., Wang D., Many M.-C. Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J. Biol. Chem. 2000. V. 275. P. 23227—23233.

Raspe E., Dumont J.E. Tonic modulation of dog thyrocyte H2O2 generation and I- uptake by thyrotropin through the cyclic adenosine 3’-,5’-monophosphate cascade. Endocrinology. 1995. V. 136. P. 965—973.

Geiszt M., Witta J., Baffi J., Lekstrom K., Leto T.L. Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense. FASEB J. 2003. V. 17(11). P. 1502—1504.

Raspé E., Dumont J.E. Tonic modulation of dog thyrocyte H2O2 generation and I- uptake by thyrotropin through the cyclic adenosine 3’-,5’-monophosphate cascade. Endocrinology. 1995. V. 136. P. 965—973.

Morand S., Dos Santos O.F., Ohayon. Identification of a Truncated Dual Oxidase 2 (DUOX2) Messenger Ribonucleic Acid (mRNA) in Two Rat Thyroid Cell Lines. Insulin and Forskolin Regulation of DUOX2 mRNA Levels in FRTL-5 Cells and Porcine Thyrocytes. Endocrinology. 2003. V. 144. P. 567—574.

Morand S., Chaaraoui M., Kaniewski J. Effect of Iodide on Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activity and Duox2 Protein Expression in Isolated Porcine Thyroid Follicles. Endocrinology. 2003. V. 144. P. 1241—1248.

Lacroix L., Nocera M., Mian C., Caillou B., Virion A., Dupuy C., Filetti S., Bidart J.,M., Schlumberger, M. Expression of nicotinamide adenine dinucleotide phosphate oxidase flavoprotein DUOX genes and proteins in human papillary and follicular thyroid carcinomas. Thyroid 2001. V. 11. P. 1017—1023.

Caillou B., Dupuy C., Lacroix L. Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase (ThoX, LNOX,Duox) genes and proteins in human thyroid tissues. J Clin Endocrinol Metab. 2001. V. 86(7). P. 3351-3358.

Carvalho D.P., Dupuy C., Gorin Y. The Ca2+- and reduced nicotinamide adenine dinucleotide phosphate-dependent hydrogen peroxide generating system is induced by thyrotropin in porcine thyroid cells. Endocrinology. 1996. V. 137. P. 1007-1012.

Moreno J.C., Bikker H., Kempers M.J. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. New Eng. J. Med. 2002. V 347. P. 95-102.

Baas F., van Ommen G.-J. B., Bikker H. The human thyroglobulin gene is over 300 kb long and contains introns of up to 64 kb. Nucleic Acids Res. 1986. V. 14. P. 5171-5186.

Кандрор В.И. Молекулярно-генетические аспекты тиреоидной патологии. // Пробл. Эндокринол. 2001, Т. 47. N 5. С. 3-10.

De Vijlder J.J., Baas F., Koch C.A. M. Autosomal dominant inheritance of a thyroglobulin abnormality suggests cooperation of subunits in hormone formation. Ann. Endocr. 1983. V. 44. P. 36.

Van Ommen G.B. Merging autosomal dominance and recessivity. (Letter) Am. J. Hum. Genet. 1987. V. 41. P. 689-691.

Yoshida S., Takamatsu J., Kuma K. A variant of adenomatous goiter with characteristic histology and possible hereditary thyroglobulin abnormality. J. Clin. Endocr. Metab. 1996. V. 81. P. 1961-1966.

Medeiros-Neto G., Bunduki V., Tomimori E. Prenatal diagnosis and treatment of dyshormonogenetic fetal goiter due to defective thyroglobulin synthesis. J. Clin. Endocr. Metab. 1997. V. 82. P. 4239-4242.

Cochaux P., Ieiri T., Targovnik H., Suzuki M. Identification of a splicing mutation responsible for a human hereditary goiter with hypothyroidism. Am. J. Hum. Genet. 1991. V. 49. Supp l. P. 131.

Targovnik H., Propato F., Varela V. Low levels of thyroglobulin messenger ribonucleic acid in congenital goitrous hypothyroidism with defective thyroglobulin synthesis. J. Clin. Endocr. Metab. 1989. V. 69. P. 1137-1147.

Caron P., Moya C.M., Malet D., Gutnisky V.J., Chabardes B., Rivolta C.M., Targovnik H.M. Compound heterozygous mutations in the thyroglobulin gene (1143delC and 6725G-A [R2223H]) resulting in fetal goitrous hypothyroidism. J. Clin. Endocr. Metab., 2003. V. 88. P. 3546-3553.

Hishinuma A., Takamatsu J., Ohyama Y. Two novel cysteine substitutions (C1263R and C1995S) of thyroglobulin cause a defect in intracellular transport of thyroglobulin in patients with congenital goiter and the variant type of adenomatous goiter. J. Clin. Endocr. Metab. 1999. V. 84. P. 1438-1444.

Caron P., Moya C.M., Malet D. Compound heterozygous mutations in the thyroglobulin gene (1143delC and 6725G-A [R2223H]) resulting in fetal goitrous hypothyroidism. J. Clin. Endocr. Metab. 2003. V. 88. P. 3546-3553.

Hishinuma A., Kasai K., Masawa N. Missense mutation (C1263R) in the thyroglobulin gene causes congenital goiter with mild hypothyroidism by impaired intracellular transport. Endocr J. 1998. V. 45(3). P. 315-327.

Corral J., Martin C., Perez R., Sanchez I. Thyroglobulin gene point mutation associated with non-endemic simple goitre. Lancet. 1993.V. 341. P. 462-464.

Perez-Centeno C., Gonzalez-Sarmiento R., Mories M.T., Corrales J.J., Miralles-Garcia J.M. Thyroglobulin exon 10 gene point mutation in a patient with endemic goiter. Thyroid. 1996.V. 6(5). P. 423-427.

Civitareale D., Lonigro R., Sinclair A.J., Di Lauro R. 1990 A thyroid-specific nuclear protein essential for tissue-specific expression of the thyroglobulin promoter. EMBO J. 1989. V. 8. P. 2537-2542.

Guazzi S., Price M., De Felice M., Damante G., Mattei M.-G., Di Lauro R. Thyroid nuclear factor 1 (TTF-1) contains a homeodomain and displays a novel DNA binding specificity. EMBO J. 1990. V. 9. P. 3631-3639.

Mizuno K., Gonzalez F.J., Kimura S. Thyroid-specific enhancer-binding protein (T/EBP): cDNA cloning, functional characterization, and structural identity with thyroid transcription factor TTF-1. Mol Cell Biol. 1991. V. 11. P. 4927-4933.

Francis-Lang H., Price M., Polycarpou-Schwarz M., Di Lauro R. Cell-type-specific expression of the rat thyroperoxidase promoter indicates common mechanisms for thyroid-specific gene expression. Mol Cell Biol. 1992 V. 12. P. 576-588.

Shimura H., Okajima F., Ikuyama S., Shimura Y., Kimura S., Saji M., Kohn L.D. Thyroid-specific expression and cyclic adenosine 3’,5’-monophosphate autoregulation of the thyrotropin receptor gene involves thyroid transcription factor-1. Mol Endocrinol. 1994. V. 8. P. 1049-1069.

Ohmori M., Shimura H., Shimura Y., Ikuyama S., Kohn L.D. Characterization of an up-stream thyroid transcription factor-1-binding site in the thyrotropin receptor promoter. Endocrinology. 1995. V. 136. P. 269-282.

Krude H., Schutz B., Biebermann H., von Moers A. Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-

haploinsufficiency. J. Clin. Invest. 2002. V. 109. P. 475-480.

Chadwick B.P., Obermayr F., Frischauf A.-M. FKHL15, a new human member of the forkhead gene family located on chromosome 9q22. Genomics. 1997. V. 41. P. 390-396.

Zannini M., Avantaggiato V., Biffali E. TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation. EMBO J. 1997. V. 16. P. 3185-3197.

Toublanc J.E. Comparison of epidemiological data on congenital hypothyroidism in Europe with those of other parts in the world. Horm. Res. 1992. V. 38. P. 230-235.

Bamforth J.S., Hughes I.A., Lazarus J.H., Weaver C.M., Harper P.S. Congenital hypothyroidism, spiky hair, and cleft palate. J. Med. Genet. 1989. V. 26. P. 49-60.

Mansouri A., St-Onge L., Gruss P. Role of Pax genes in endoderm-derived organs. Trends Endocr. Metab. 1999. V. 10. P. 164-167.

Pasca di Magliano M., Di Lauro R., Zannini M. Pax8 has a key role in thyroid cell differentiation. Proc. Nat. Acad. Sci. 2000. V. 97.P. 13144-13149.

Kroll T.G., Sarraf P., Pecciarini L., Chen C.J., Mueller E., Spiegelman B.M., Fletcher J.A. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma. J Clin Endocrinol Metab. 2001 V. 86(8). P. 3962-3967.

Ohmori M., Ohta M., Shimura H., Shimura Y. Cloning of the single strand DNA-binding protein important for maximal expression and thyrotropin (TSH)-induced negative regulation of the TSH receptor. Molec. Endocr., 1996. V. 10. P. 1407-1424.

The authors declare that there are no conflicts of interest present.