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      Identification of Novel Genes Involved in Congenital Hypothyroidism Using Serial Analysis of Gene Expression

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          Part of the molecular basis of congenital hypothyroidism (CH) has been elucidated by the identification of molecular defects in pituitary- and thyroid-specific genes in patients with various subtypes of hypothyroidism. So far identified genetic defects only explain a small proportion of cases of hypothyroidism. Thus novel research strategies are required to isolate more tissue-specific genes involved in the pathogenesis of CH at present considered ‘idiopathic’ from a molecular perspective. We applied serial analysis of gene expression to human thyroid tissue and developed a computational substraction method to identify tissue-specific genes. The result has been the identification of three genes preferentially expressed in the thyroid gland. The first one encodes part of the thyroid oxidase (THOX2) system. We linked mutations in the THOX2 gene with idiopathic cases of transient and permanent CH. The second transcript identified, DEHAL1, encodes the protein responsible for the recycling of iodine in the thyroid gland and represents the candidate gene for a specific subtype of CH. The third one encodes NM41, a protein currently under investigation which shows features characteristic of the cystine-knot family of proteins, typically involved in early development.

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          Most cited references 8

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          Incorrect use of the term synteny.

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            Purification of a Novel Flavoprotein Involved in the Thyroid NADPH Oxidase

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              Characterization of ThOX proteins as components of the thyroid H(2)O(2)-generating system.

              We have recently cloned two thyroid-specific cDNAs encoding new members of the NADPH oxidase family. ThOX1 and ThOX2 proteins are colocalized with thyroperoxidase at the apical membrane of human thyroid cells. In the present study we have determined their subcellular localization and maturation in relation to their enzymatic activity. A majority of ThOX proteins accumulated inside the cell and only a small fraction was expressed at the surface. Western blots demonstrated that ThOX's are glycoproteins of 180,000 and 190,000. When totally deglycosylated the molecular weight of both ThOX1 and ThOX2 drops to 160,000. Ca(2+) stimulates the basal H(2)O(2) generation in PC Cl3 cells at a level corresponding to 20% of the leukocyte H(2)O(2) production stimulated by PMA. Nonthyroid cell lines transfected with ThOX1 and ThOX2 show only a single immunoreactive band in Western blot analysis, corresponding to the protein of 180,000. This "immature" protein remains exclusively intracellular and does not present any enzymatic activity. This is not modified by coexpression of thyroperoxidase and p22(Phox). Transfection of ThOX cDNAs into PLB-XCGD cells does not reconstitute their NADPH oxidase activity. We conclude that (1) the thyroid contains some elements of the leukocyte H(2)O(2)-generating system but not all of them; (2) ThOX's are predominantly or exclusively located inside the cell in thyrocytes or in transfected cells, respectively, and as such they are inactive; (3) ThOX's cannot replace gp91(Phox) in the leukocyte; and (4) the thyroid H(2)O(2)-generating system is analogous to the leukocyte system with regard to ThOX's and gp91(Phox) but very different in other aspects. Additional thyroid-specific components are probably required to get complete protein processing and full enzymatic activity in the thyroid. ©2002 Elsevier Science (USA).

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                December 2003
                17 November 2004
                : 60
                : Suppl 3
                : 96-102
                Amsterdam, The Netherlands
                74509 Horm Res 2003;60(suppl 3):96–102
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 3, References: 22, Pages: 7
                ESPE Research Fellowship Grant Lecture andPlenary Lecture


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