Journal of Isfahan Medical School

Journal of Isfahan Medical School

The Mutation of Dual Oxidase 2 (DUOX2) Gene among Patients with Permanent and Transient Congenital Hypothyroidism

Document Type : Original Article(s)

Authors
Nooshin Rostampour 1
Mohamadhasan Tajaddini 2
Mahin Hashemipour 3
Mansour Salehi 4
Avat Feizi 5
Shaghayegh Haghjooy Javanmard 6
Roya Kelishadi 7
Hosein Saneian 8
Silva Hovsepian 9
Massoud Amini 10
1 Resident of Pediatrics Endocrinology, Department of Pediatrics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
2 MSc Student, Student Research Committee, Department of Clinical Biochemistry, School of Pharmacy and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
3 Professor, Endocrine and Metabolism Research Center, Child Health Promotion Research Center, Department of Pediatrics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
4 Assosiate Professor, Department. of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
5 Assistant Professor, Department of Epidemiology and biostatics, School of Public Health, Isfahan University of Medical Sciences, Isfahan, Iran.
6 Assistant Professor, Applied Physiology Research Center and Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
7 Professor, Department of Pediatrics, Child Health Promotion Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
8 Assistant Professor, Department of Pediatrics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
9 General Practitioner, Research Assistant, Child Health Promotion Research Center, Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
10 Professor, Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
Abstract
Background: Considering the high prevalence of congenital hypothyroidism (CH) in Isfahan and its different etiologies comparing with other countries, the high rate of parental consanguinity and the role of DUOX2 gene in transient CH and permanent CH due to dyshormonogenesis, the aim of this research was to investigate the mutations of DUOX2 gene in patients with transient or permanent CH due to dyshormonogenesis.Methods: In this descriptive prospective study, patients diagnosed with transient CH and permanent CH due to dyshormonogenesis during CH screening program, were selected. Venous blood sample was obtained to determine the 3 mutations Q36H, R376W, D506N of DUOX2 gene using PCR method by specific primers and complementary methods such as Restriction fragment length polymorphism (RFLP) and Single-strand conformation polymorphism (SSCP).Finding: In this study 25 and 33 CH patients with transient CH and permanent CH due to dyshormonogenesis were studied respectively. 30 children studied as control group. We did not find any mutation of the mentioned three mutations of DUOX2 gene.  Conclusion: Considering the findings of current study, it seems that further studies with other methods and also with considering other gene mutations such as pendrin, NIS and thyroglobulin is needed for more accurate conclusion. 
Keywords
Congenital hypothyroidism
Dual Oxidase 2 (DUOX2) gene
  1. Knobel M, Medeiros-Neto G. An outline of inherited disorders of the thyroid hormone generating system. Thyroid 2003; 13(8): 771-801.
  2. Grant DB, Smith I, Fuggle PW, Tokar S, Chapple J. Congenital hypothyroidism detected by neonatal screening: relationship between biochemical severity and early clinical features. Arch Dis Child 1992; 67(1): 87-90.
  3. Castanet M, Polak M, Bonaiti-Pellie C, Lyonnet S, Czernichow P, Leger J. Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors. J Clin Endocrinol Metab 2001; 86(5): 2009-14.
  4. Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet 2005; 42(5): 379-89.
  5. Abramowicz MJ, Targovnik HM, Varela V, Cochaux P, Krawiec L, Pisarev MA, et al. Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter. J Clin Invest 1992; 90(4): 1200-4.
  6. Ieiri T, Cochaux P, Targovnik HM, Suzuki M, Shimoda S, Perret J, et al. A 3' splice site mutation in the thyroglobulin gene responsible for congenital goiter with hypothyroidism. J Clin Invest 1991; 88(6): 1901-5.
  7. Fujiwara H, Tatsumi K, Miki K, Harada T, Miyai K, Takai S, et al. Congenital hypothyroidism caused by a mutation in the Na+/I- symporter. Nat Genet 1997; 16(2): 124-5.
  8. Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 1997; 17(4): 411-22.
  9. Nose O, Harada T, Miyai K, Hata N, Ogawa M, Maki I, et al. Transient neonatal hypothyroidism probably related to immaturity of thyroidal iodine organification. J Pediatr 1986; 108(4): 573-6.
  10. Dupuy C, Ohayon R, Valent A, Noel-Hudson MS, Deme D, Virion A. Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. Cloning of the porcine and human cdnas. J Biol Chem 1999; 274(52): 37265-9.
  11. De D, X, Wang D, Many MC, Costagliola S, Libert F, Vassart G, et al. Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J Biol Chem 2000; 275(30): 23227-33.
  12. Kusakabe T. Deficient cytochrome b5 reductase activity in nontoxic goiter with iodide organification defect. Metabolism 1975; 24(10): 1103-13.
  13. Niepomniszcze H, Targovnik HM, Gluzman BE, Curutchet P. Abnormal H2O2 supply in the thyroid of a patient with goiter and iodine organification defect. J Clin Endocrinol Metab 1987; 65(2): 344-8.
  14. Figueiredo MD, Cardoso LC, Ferreira AC, Campos DV, Da Cruz DM, Corbo R, et al. Goiter and hypothyroidism in two siblings due to impaired Ca(+2)/NAD(P)H-dependent H(2)O(2)-generating activity. J Clin Endocrinol Metab 2001; 86(10): 4843-8.
  15. Moreno JC, Bikker H, Kempers MJ, Van Trotsenburg AS, Baas F, De Vijlder JJ, et al. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med 2002; 347(2): 95-102.
  16. Maruo Y, Takahashi H, Soeda I, Nishikura N, Matsui K, Ota Y, et al. Transient congenital hypothyroidism caused by biallelic mutations of the dual oxidase 2 gene in Japanese patients detected by a neonatal screening program. J Clin Endocrinol Metab 2008; 93(11): 4261-7.
  17. Hashemipour M, Hovsepian S, Kelishadi R, Iranpour R, Hadian R, Haghighi S, et al. Permanent and transient congenital hypothyroidism in Isfahan-Iran. J Med Screen 2009; 16(1): 11-6.
  18. Hashemipour M, Amini M, Talaie M, Kelishadi R, Hovespian S, Iranpour R, et al. Parental consanguinity among parents of neonates with congenital hypothyroidism in Isfahan. East Mediterr Health J 2007; 13(3): 567-74.
  19. Johnson KR, Marden CC, Ward-Bailey P, Gagnon LH, Bronson RT, Donahue LR. Congenital hypothyroidism, dwarfism, and hearing impairment caused by a missense mutation in the mouse dual oxidase 2 gene, Duox2. Mol Endocrinol 2007; 21(7): 1593-602.
  20. Ohye H, Sugawara M. Dual oxidase, hydrogen peroxide and thyroid diseases. Exp Biol Med (Maywood) 2010; 235(4): 424-33.
  21. Vigone MC, Fugazzola L, Zamproni I, Passoni A, Di Candia S, Chiumello G, et al. Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings. Hum Mutat 2005; 26(4): 395.
  22. Grasberger H, De D, X, Miot F, Pohlenz J, Refetoff S. Missense mutations of dual oxidase 2 (DUOX2) implicated in congenital hypothyroidism have impaired trafficking in cells reconstituted with DUOX2 maturation factor. Mol Endocrinol 2007; 21(6): 1408-21.
  23. Varela V, Rivolta CM, Esperante SA, Gruneiro-Papendieck L, Chiesa A, Targovnik HM. Three mutations (p.Q36H, p.G418fsX482, and g.IVS19-2A>C) in the dual oxidase 2 gene responsible for congenital goiter and iodide organification defect. Clin Chem 2006; 52(2): 182-91.
  24. Pfarr N, Korsch E, Kaspers S, Herbst A, Stach A, Zimmer C, et al. Congenital hypothyroidism caused by new mutations in the thyroid oxidase 2 (THOX2) gene. Clin Endocrinol (Oxf) 2006; 65(6): 810-5.
  25. Tonacchera M, De Marco G, Agretti P, Monta-
  26. nelli L, Di Cosmo C, Freitas Ferreira AC, et al. Identification and functional studies of two new dual-oxidase 2 (DUOX2) mutations in a child with congenital hypothyroidism and a eutopic normal-size thyroid gland. J Clin Endocrinol Metab 2009; 94(11): 4309-14.
  27. Niu DM, Hwang B, Chu YK, Liao CJ, Wang PL, Lin CY. High prevalence of a novel mutation (2268 insT) of the thyroid peroxidase gene in Taiwanese patients with total iodide organification defect, and evidence for a founder effect. J Clin Endocrinol Metab 2002; 87(9): 4208-12.
Journal of Isfahan Medical School
Volume 29, Issue 139 - Serial Number 139
March and April 2011
Pages 588-595

  • Receive Date 15 June 2011
  • Accept Date 06 April 2022