Yonsei Med J.  2017 Jul;58(4):888-890. 10.3349/ymj.2017.58.4.888.

Compound Heterozygous Mutations in the DUOX2/DUOXA2 Genes Cause Congenital Hypothyroidism

• Zheng X
• Ma SG
• Guo ML
• Qiu YL
• Yang LX

• KMID: 2419100
• DOI: http://doi.org/10.3349/ymj.2017.58.4.888

Abstract

The mutations in the dual oxidase 2 (DUOX2) and dual oxidase maturation factor 2 (DUOXA2) genes can cause congenital hypothyroidism (CH). This study reports the pedigree with goitrous congenital hypothyroidism (GCH) due to the coexistence of heterozygous mutations in the DUOX2 and DUOXA2 genes. The two sisters with GCH were diagnosed with CH at neonatal screening and were enrolled in this study. The DUOX2, DUOXA2, and thyroid peroxidase (TPO) genes were considered for genetic defects screening. Family members of the patients and normal controls were also enrolled and evaluated. The two girls harbored compound heterozygous mutations, including a new mutation of c.2654G>T (p.R885L) in the maternal DUOX2 allele and c.738C>G (p.Y246X) in the paternal DUOXA2 allele, that has been previously reported. The germline mutations from the families were consistent with an autosomal recessive inheritance pattern. No mutations in the TPO gene and the controls were observed.

Keyword

Congenital hypothyroidism; dual oxidase 2; dual oxidase maturation factor 2; mutation

MeSH Terms

Base Sequence
Congenital Hypothyroidism/blood/*genetics
Dual Oxidases
Exons/genetics
Family
Female
*Genetic Predisposition to Disease
Heterozygote
Humans
Infant, Newborn
Male
Membrane Proteins/*genetics
Mutation/*genetics
NADPH Oxidases/*genetics
Pedigree
Membrane Proteins
Dual Oxidases
NADPH Oxidases

Figure

• 

  Fig. 1 Genotypes indicating the pedigrees with congenital hypothyroidism due to the coexistence of heterozygous mutations, c.2654G>T (p.R885L) in the DUOX2 gene and c.738C>G (p.Y246X) in the DUOXA2.

Reference

1. Anjum A, Afzal MF, Iqbal SM, Sultan MA, Hanif A. Congenital hypothyroidism in neonates. Indian J Endocrinol Metab. 2014; 18:213–216. PMID: 24741519.

2. Szinnai G. Genetics of normal and abnormal thyroid development in humans. Best Pract Res Clin Endocrinol Metab. 2014; 28:133–150. PMID: 24629857.

3. Corvilain B, van Sande J, Laurent E, Dumont JE. The H2O2-generating system modulates protein iodination and the activity of the pentose phosphate pathway in dog thyroid. Endocrinology. 1991; 128:779–785. PMID: 1846588.

4. Grasberger H, Refetoff S. Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent. J Biol Chem. 2006; 281:18269–18272. PMID: 16651268.

5. Grasberger H. Defects of thyroidal hydrogen peroxide generation in congenital hypothyroidism. Mol Cell Endocrinol. 2010; 322:99–106. PMID: 20122987.

6. Yi RH, Zhu WB, Yang LY, Lan L, Chen Y, Zhou JF, et al. A novel dual oxidase maturation factor 2 gene mutation for congenital hypothyroidism. Int J Mol Med. 2013; 31:467–470. PMID: 23292166.

7. Wang F, Lu K, Yang Z, Zhang S, Lu W, Zhang L, et al. Genotypes and phenotypes of congenital goitre and hypothyroidism caused by mutations in dual oxidase 2 genes. Clin Endocrinol (Oxf). 2014; 81:452–457. PMID: 24735383.

8. 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; 93:4261–4267. PMID: 18765513.

9. Hulur I, Hermanns P, Nestoris C, Heger S, Refetoff S, Pohlenz J, et al. A single copy of the recently identified dual oxidase maturation factor (DUOXA) 1 gene produces only mild transient hypothyroidism in a patient with a novel biallelic DUOXA2 mutation and monoallelic DUOXA1 deletion. J Clin Endocrinol Metab. 2011; 96:E841–E845. PMID: 21367925.

10. 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; 87:4208–4212. PMID: 12213873.

11. Ris-Stalpers C, Bikker H. Genetics and phenomics of hypothyroidism and goiter due to TPO mutations. Mol Cell Endocrinol. 2010; 322:38–43. PMID: 20153806.

12. Ma SG, Wu XJ, Liu H, Xu W, He L. Mutations of the thyroid peroxidase gene in Chinese siblings with congenital goitrous hypothyroidism. Arq Bras Endocrinol Metabol. 2012; 56:614–617. PMID: 23329183.

13. O'Neill S, Brault J, Stasia MJ, Knaus UG. Genetic disorders coupled to ROS deficiency. Redox Biol. 2015; 6:135–156. PMID: 26210446.

14. Wang F, Lu K, Yang Z, Zhang S, Lu W, Zhang L, et al. Genotypes and phenotypes of congenital goitre and hypothyroidism caused by mutations in dual oxidase 2 genes. Clin Endocrinol (Oxf). 2014; 81:452–457. PMID: 24735383.

15. Zamproni I, Grasberger H, Cortinovis F, Vigone MC, Chiumello G, Mora S, et al. Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism. J Clin Endocrinol Metab. 2008; 93:605–610. PMID: 18042646.