Inactivating Mutations in the Gene for Thyroid Oxidase 2 (<i>THOX2</i>) and Congenital Hypothyroidism

Moreno, J.C.; Bikker, Hennie; Kempers, Marlies; Trotsenburg, A S Paul van; Baas, Frank; Vijlder, J. J. M. De; Vulsma, Thomas; Ris‐Stalpers, Carrie

doi:10.1056/nejmoa012752

Cited by 444 publications

(359 citation statements)

References 44 publications

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“…The H 2 O 2 -generating system associated with TPO is a calcium-dependent NADPH:O 2 oxidoreductase, which has a catalytic core containing a 1548-amino acid integral membrane flavoprotein encoded by the DUOX2 gene (3)(4)(5). A biallele inactivating mutation on the DUOX2 gene was found in a patient with a total iodide organification defect; this confirmed the essential role of Duox2, probably as a supplier of H 2 O 2 for TPO (6). The DUOX1 gene, situated near DUOX2 on chromosome 15q15, encodes a homologous 1551-amino acid protein displaying 83% sequence similarity (5).…”

mentioning

confidence: 66%

Targeting of the Dual Oxidase 2 N-terminal Region to the Plasma Membrane

Morand

Agnandji

Noël-Hudson

et al. 2004

Journal of Biological Chemistry

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-generating system has yet been obtained after transfecting Duox2 into non-thyroid cell lines, because it is retained in the endoplasmic reticulum (ER). We investigated the level of maturation of various Duox2 truncated proteins in an attempt to identify the region of Duox2 responsible for its remaining in the ER. Duox2-Q686X mutant, corresponding to the Nterminal ectodomain including the first putative transmembrane domain, was expressed in different cell lines. Carbohydrate content analysis revealed that complex type-specific Golgi apparatus (GA) oligosaccharides were present on pig Duox2-Q686X, whereas human truncated Duox2 carried only high mannose-type sugar chains characteristic of the ER. Further characterization using surface biotinylation and flow cytometry assays indicated that pig Duox2-Q686X was present at the plasma membrane, whereas human Duox2-Q686X remained inside the cell. The replacement of the last 90 residues of the human Duox2-Q686X with the pig equivalent region allowed the chimerical peptide to reach the Golgi apparatus. Pig mutants containing the complete first intracellular loop with or without the second transmembrane domain accumulated in the ER. These findings show that 1) the human Duox2-Q686X region encompassing residues 596 -685 prevents mutant exportation from the ER and 2) there is a pig Duox2 retention domain in the first intracellular loop. In addition, missense mutations of four cysteines (Cys-351, -370, -568, or -582) completely inhibited the emergence of pig Duox2-Q686X from the ER compartment, indicating their importance in Duox2 maturation.

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mentioning

confidence: 66%

Targeting of the Dual Oxidase 2 N-terminal Region to the Plasma Membrane

Morand

Agnandji

Noël-Hudson

et al. 2004

Journal of Biological Chemistry

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“…Duox was first shown to be this longsought oxidase based on purification and partial cDNA cloning [187]; two forms of this oxidase were subsequently identified by molecular cloning [188][189][190], and both are expressed in thyroid [191]. The essential role for Duox2 in thyroid hormone biosynthesis is demonstrated conclusively by the occurrence of mutations in this gene in genetic variants of hypothyroidism [192,193].…”

Section: Nox Enzymes and The Endocrine System A Duox And The Thyroidmentioning

confidence: 99%

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Lambeth¹

2007

Free Radical Biology and Medicine

590

454

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“…The H 2 O 2 that is responsible for TPO activation originates from the NOX homologues DUOX1 and DUOX2 that are highly expressed within thyrocytes (27). The importance of DUOX2 in thyroid hormone synthesis is supported by clinical observations of hypothyroidism in association with missense mutations in the DUOX2 gene (28,29). DUOX1 and 2 are also expressed in airway and intestinal epithelia, where they may contribute to host defense by a similar cooperative mechanism with lactoperoxidase (LPO), which is secreted by submucosal glands (1,30,31).…”

Section: Targets For Nox-derived Ros: Heme Peroxidasesmentioning

confidence: 99%

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

Vliet

2008

Free Radical Biology and Medicine

187

192

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The deliberate production of reactive oxygen species (ROS) by phagocyte NADPH oxidase is widely appreciated as a critical component of antimicrobial host defense. Recently, additional homologs of NADPH oxidase (NOX) have been discovered throughout the animal and plant kingdoms, which appear to possess diverse functions in addition to host defense, including cell proliferation, differentiation, and regulation of gene expression. Several of these NOX homologs are also expressed within the respiratory tract, where they participate in innate host defense as well as in epithelial and inflammatory cell signaling and gene expression, and fibroblast and smooth muscle cell proliferation, in response to bacterial or viral infection and environmental stress. Inappropriate expression or activation of NOX/DUOX during various lung pathologies suggests their specific involvement in respiratory disease. This review summarizes the current state of knowledge regarding the general functional properties of mammalian NOX enzymes, and their specific importance in respiratory tract physiology and pathology.

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Inactivating Mutations in the Gene for Thyroid Oxidase 2 (THOX2) and Congenital Hypothyroidism

Cited by 444 publications

References 44 publications

Targeting of the Dual Oxidase 2 N-terminal Region to the Plasma Membrane

Targeting of the Dual Oxidase 2 N-terminal Region to the Plasma Membrane

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

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