title: Genetic defects of hydrogen peroxide generation in the thyroid gland.
abstract: Hydrogen peroxide (H2O2) is a key element in thyroid hormone biosynthesis. It is the substrate used by thyroid peroxidase for oxidation and incorporation of iodine into thyroglobulin, a process known as organification. The main enzymes composing the H2O2-generating system are the dual oxidase 2 (DUOX2) and the recently described DUOX maturation factor 2 (DUOXA2). Defects in these reactions lead to reduced thyroid hormone synthesis and hypothyroidism, with consequent increased TSH secretion and goiter. Since the first report in 2002 of DUOX2 mutations causing congenital hypothryoidism (CH), to date 25 different mutations have been described. Affected patients show a positive perchlorate discharge test and high phenotypic variability, ranging from transient to permanent forms of CH. Up to now, only two cases of CH due to DUOXA2 defects have been published. They also suggest the existence of a great genotype-phenotype variability. The phenotypic expression is probably influenced by genetic background and environmental factors. DUOX and DUOXA constitute a redundant system in which DUOX1/DUOXA1 can at least partially replace the function of DUOX2/DUOXA2. Furthermore, increased nutritional iodide could ensure a better use of H2O2 provided by DUOX1.
authors: Department of Pediatric Endocrinology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, via Olgettina 60, 20132 Milan, Italy. weber.giovanna@hsr.it
authors: G
authors: G
authors: Weber
authors: S
authors: S
authors: Rabbiosi
authors: I
authors: I
authors: Zamproni
authors: L
authors: L
authors: Fugazzola
mesh_terms: D000818:Animals; D003409:Congenital Hypothyroidism / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D000074623:Dual Oxidases; D030342:Genetic Diseases, Inborn / Q000150:complications / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics; D008659:Metabolic Diseases / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics; D019255:NADPH Oxidases / Q000235:genetics / Q000502:physiology; D013961:Thyroid Gland / Q000378:metabolism* / Q000502:physiology; D013963:Thyroid Hormones / Q000096:biosynthesis
chemical_list: C513411:DUOXA2 protein, human; D008565:Membrane Proteins; D013963:Thyroid Hormones; D006861:Hydrogen Peroxide; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human
references: J Clin Endocrinol Metab. 2008 Nov;93(11):4261-7
references: 18765513
references: J Clin Endocrinol Metab. 2009 Nov;94(11):4309-14
references: 19789206
references: Thyroid. 2008 May;18(5):561-6
references: 18426362
references: Am J Respir Cell Mol Biol. 2005 May;32(5):462-9
references: 15677770
references: Science. 2005 Nov 4;310(5749):847-50
references: 16272120
references: Mol Cell Endocrinol. 2004 Feb 12;214(1-2):53-62
references: 15062544
references: Physiol Rev. 2007 Jan;87(1):245-313
references: 17237347
references: J Thyroid Res. 2010 Jan 28;2010:101948
references: 21048833
references: Am J Physiol Gastrointest Liver Physiol. 2005 May;288(5):G933-42
references: 15591162
references: J Clin Endocrinol Metab. 2007 Oct;92(10):3764-73
references: 17666482
references: Clin Chem. 2006 Feb;52(2):182-91
references: 16322276
references: Hum Mutat. 2005 Oct;26(4):395
references: 16134168
references: J Clin Endocrinol Metab. 2011 Nov;96(11):E1838-42
references: 21900383
references: Mol Endocrinol. 2012 Mar;26(3):481-92
references: 22301785
references: J Clin Endocrinol Metab. 2008 Feb;93(2):605-10
references: 18042646
references: J Med Genet. 2005 May;42(5):379-89
references: 15863666
references: J Biol Chem. 2009 Mar 13;284(11):6725-34
references: 19144650
references: Clin Endocrinol (Oxf). 2006 Dec;65(6):810-5
references: 17121535
references: Mol Endocrinol. 2007 Jun;21(6):1408-21
references: 17374849
references: J Endocrinol. 1998 Feb;156(2):315-22
references: 9518878
references: FASEB J. 2003 Aug;17(11):1502-4
references: 12824283
references: J Clin Endocrinol Metab. 2011 May;96(5):E841-5
references: 21367925
references: J Biol Chem. 2004 Aug 27;279(35):36454-61
references: 15210697
references: Clin Sci (Lond). 2006 Jul;111(1):1-20
references: 16764554
references: J Biol Chem. 2005 Aug 26;280(34):30046-54
references: 15972824
references: Curr Opin Pediatr. 2001 Aug;13(4):364-72
references: 11717564
references: Endocrinology. 1984 Jul;115(1):392-8
references: 6329661
references: Endocrinology. 2006 Jul;147(7):3391-7
references: 16627585
references: J Biol Chem. 2000 Jul 28;275(30):23227-33
references: 10806195
references: J Biol Chem. 1999 Dec 24;274(52):37265-9
references: 10601291
references: N Engl J Med. 2002 Jul 11;347(2):95-102
references: 12110737
references: Endocr Rev. 2005 Dec;26(7):944-84
references: 16174820
references: J Biol Chem. 2006 Jul 7;281(27):18269-72
references: 16651268
references: Clin Endocrinol (Oxf). 2009 Nov;71(5):739-45
references: 19486019
references: J Cell Biol. 2001 Aug 20;154(4):879-91
references: 11514595
references: Horm Res. 2003;60 Suppl 3:96-102
references: 14671405
references: Mol Cell Endocrinol. 2010 Jun 30;322(1-2):72-82
references: 20083154
references: Cancer Res. 2008 Feb 15;68(4):1037-45
references: 18281478
references: J Clin Endocrinol Metab. 2010 Sep;95(9):4283-90
references: 20591982
references: Curr Opin Pediatr. 2011 Aug;23(4):421-8
references: 21543982
references: J Clin Endocrinol Metab. 2011 Aug;96(8):E1335-9
references: 21565790
references: Mol Genet Metab. 2007 Jul;91(3):268-77
references: 17512233
references: Hum Mutat. 2010 Apr;31(4):E1304-19
references: 20187165