A truncating DUOX2 mutation (R434X) causes severe congenital hypothyroidism
-
Hakan Cangul
,
Zehra Aycan
Abstract
Mutations in DUOX2 have been reported to cause congenital hypothyroidism (CH), and our aim in this study was to determine the genetic basis of CH in two affected individuals coming from a consanguineous family. Because CH is usually inherited in autosomal recessive manner in consanguineous/multicase families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First, we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in linked genes by Sanger sequencing. The family showed potential linkage to DUOX2 locus and we detected a nonsense mutation (R434X) in both cases and the mutation segregated with disease status in the family. This study highlights the importance of molecular genetic studies in the definitive diagnosis and classification of CH, and it also suggests a new clinical testing strategy using next-generation sequencing in all primary CH cases.
Acknowledgments
This study was funded by European Union under its Framework 7 programme, FP7-PEOPLE- 2009-Marie Curie-IEF. We thank the families for their participation in this study.
References
1. Medeiros-Neto G, Knobel M, DeGroot LJ. Genetic disorders of the thyroid hormone system. In: Baxter JD, editor. Genetics in endocrinology. Philadelphia: Lippincott Williams & Wilkins, 2002;375–402.Suche in Google Scholar
2. Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet 2005;42:379–89.Suche in Google Scholar
3. Castanet M, Polak M, Bonaiti-Pellie C, Lyonnet S, Czernichow P, et al. Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors. J Clin Endocrinol Metab 2001;84:2502–6.Suche in Google Scholar
4. Kopp P. Genetic defects in the etiology of congenital hypothyroidism. Endocrinology 2002;143:2019–24.Suche in Google Scholar
5. Caputo M, Rivolta CM, Esperante SA, Gruneiro-Papendieck L, Chiesa A, et al. Congenital hypothyroidism with goitre caused by new mutations in the thyroglobulin gene. Clin Endocrinol (Oxf) 2007;67:351–7.Suche in Google Scholar
6. Grasberger H, Refetoff S. Genetic causes of congenital hypothyroidism due to dyshormonogenesis. Curr Opin Pediatr 2001;23:421–8.Suche in Google Scholar
7. Targovnik HM, Esperante SA, Rivolta CM. Genetics and phenomics of hypothyroidism and goiter due to thyroglobulin mutations. Mol Cell Endocrinol 2010;322:44–55.Suche in Google Scholar
8. Ris-Stalpers C, Bikker H. Genetics and phenomics of hypothyroidism and goiter due to TPO mutations. Mol Cell Endocrinol 2010;322:38–43.Suche in Google Scholar
9. Belforte FS, Miras MB, Olcese MC. Congenital goitrous hypothyroidism: mutation analysis in the thyroid peroxidase gene. Clin Endocrinol 2012;76:568–76.Suche in Google Scholar
10. 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. Endocrinology 1991;128:779–85.Suche in Google Scholar
11. Kusakabe T. Deficient cytochrome b5 reductase activity in nontoxic goiter with iodide organification defect. Metabolism 1975;24:1103–13.Suche in Google Scholar
12. 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;65:344–48.Suche in Google Scholar
13. Figueiredo MD, Cardoso LC, Ferreira AC, Campos DV, da Cruz Domingos M, et al. Goiter and hypothyroidism in two siblings due to impaired Ca2/NAD(P)H-dependent H2O2-generating activity. J Clin Endocrinol Metab 2001;86:4843–8.Suche in Google Scholar
14. Dupuy C, Ohayon R, Valent A, Noel-Hudson MS, Deme D, et al. Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. J Biol Chem 1999;274:37265–91.Suche in Google Scholar
15. De Deken X, Wang D, Costagliola S. Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J Biol Chem 2000;275:23227–33.Suche in Google Scholar
16. Moreno JC, Bikker H, Kempers MJ, van Trotsenburg AS, Baas F, et al. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med 2002;347:95–102.Suche in Google Scholar
17. Grasberger H. Defects of thyroidal hydrogen peroxide generation in congenital hypothyroidism. Mol Cell Endocrinol 2010;322:99–106.Suche in Google Scholar
18. Cangul H, Aycan Z, Olivera-Nappa A, Saglam H, Schoenmakers NA, et al. Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community. Clin Endocrinol (Oxf) 2012;79:275–81.Suche in Google Scholar
19. Baş VN, Cangul H, Agladioglu SY, Kendall M, Cetinkaya S, et al. Mild and severe congenital primary hypothyroidism in two patients by thyrotropine receptor (TSHR) gene mutation. J Pediatr Endocrinol Metabol 2012;25:1153–6.Suche in Google Scholar
20. Cangul H, Aycan Z, Saglam H, Forman JR, Cetinkaya S, et al. TSHR is the main causative-locus in autosomal recessively inherited thyroid dysgenesis. J Pediatr Endocrinol Metabol 2012;25:419–26.Suche in Google Scholar
21. Cangul H, Morgan NV, Forman JR, Saglam H, Aycan Z, et al. Novel TSHR mutations in consanguineous families with congenital non-goitrous hypothyroidism. Clin Endocrinol (Oxf) 2010;73:671–7.Suche in Google Scholar
22. Cangul H, Saglam H, Aycan Z, Yakut T, Gulten T, et al. Locus heterogeneity and mutations in thyrotropin receptor gene in autosomal recessively inherited congenital hypothyroidism. J Med Genet 2010;47:S59.Suche in Google Scholar
23. Cangul H, Boelaert K, Dogan M, Saglam Y, Kendall M, et al. Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism. Endocrine 2013 doi: 10.1007/s12020-013-0027-7.Suche in Google Scholar
©2014 by Walter de Gruyter Berlin Boston
Artikel in diesem Heft
- Masthead
- Masthead
- Images in pediatric endocrinology
- Leprechaunism (Donohue syndrome): report of a case in a newborn
- Original articles
- Children and adolescents with type 1 diabetes in Germany are more overweight than healthy controls: results comparing DPV database and CrescNet database
- Age of onset of pubertal maturation of Thai boys
- Plasma leptin and adiponectin concentrations correlate with cardiometabolic risk and systemic inflammation in healthy, non-obese children
- Early differentiation between good and poor response to growth hormone therapy in short children born small for gestational age (SGA) to improve the outcome of poor responders
- Children and adolescents with type 1 diabetes mellitus have a sixfold greater risk for prolonged QTc interval
- Effect of micronutrient supplementation on height velocity of underprivileged girls in comparison with un-supplemented healthy controls
- Insulin resistance in young adults born small for gestational age (SGA)
- The effect of childhood obesity on cardiac functions
- Adiponectin serum concentrations in newborn at delivery appear to be of fetal origin
- Thalassaemic Osteopathy: a cross-sectional preliminary study from Sri Lanka
- Health-related quality of life in Turner syndrome and the influence of key features
- Clinical analysis on 33 patients with hypothalamic syndrome in Chinese children
- The relationship between thyroid dose and diagnosis of primary hypothyroidism in pediatric brain tumor patients receiving craniospinal irradiation
- Molecular characterization of Chilean patients with a clinical diagnosis of Noonan syndrome
- Expensive therapies in children: benefit versus cost of combined treatment of recombinant human growth hormone and gonadotropin-releasing hormone analogue in girls with poor height potential
- The absence of mutations in homeobox candidate genes HOXA3, HOXB3, HOXD3 and PITX2 in familial and sporadic thyroid hemiagenesis
- A truncating DUOX2 mutation (R434X) causes severe congenital hypothyroidism
- Heterozygous GHR gene mutation in a child with idiopathic short stature
- A novel compound mutation of CYP27B1 in a Chinese family with vitamin D-dependent rickets type 1A
- A de novo mutation of DAX1 in a boy with congenital adrenal hypoplasia without hypogonadotropic hypogonadism
- Patient reports
- Hypercalcemia and osteolytic lesions as presenting symptoms of acute lymphoblastic leukemia in childhood. The use of zoledronic acid and review of the literature
- Preterm ovarian hyperstimulation syndrome presented with vaginal bleeding: a case report
- Pituitary stalk lesion in a 13-year-old female
- Radiologic manifestation of a BCS1L-mutated patient
- Permanent neonatal diabetes mellitus caused by a novel mutation in the KCNJ11 gene
- NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients
- A teenage boy with hypocalcemia after radioablation for Graves’ disease
- Short communication
- A common thyroid peroxidase gene mutation (G319R) in Turkish patients with congenital hypothyroidism could be due to a founder effect
- Letter to the Editor
- Endometriosis and migraine: what is there behind the scenes?
- 10.1515/jpem-2014-0999
Artikel in diesem Heft
- Masthead
- Masthead
- Images in pediatric endocrinology
- Leprechaunism (Donohue syndrome): report of a case in a newborn
- Original articles
- Children and adolescents with type 1 diabetes in Germany are more overweight than healthy controls: results comparing DPV database and CrescNet database
- Age of onset of pubertal maturation of Thai boys
- Plasma leptin and adiponectin concentrations correlate with cardiometabolic risk and systemic inflammation in healthy, non-obese children
- Early differentiation between good and poor response to growth hormone therapy in short children born small for gestational age (SGA) to improve the outcome of poor responders
- Children and adolescents with type 1 diabetes mellitus have a sixfold greater risk for prolonged QTc interval
- Effect of micronutrient supplementation on height velocity of underprivileged girls in comparison with un-supplemented healthy controls
- Insulin resistance in young adults born small for gestational age (SGA)
- The effect of childhood obesity on cardiac functions
- Adiponectin serum concentrations in newborn at delivery appear to be of fetal origin
- Thalassaemic Osteopathy: a cross-sectional preliminary study from Sri Lanka
- Health-related quality of life in Turner syndrome and the influence of key features
- Clinical analysis on 33 patients with hypothalamic syndrome in Chinese children
- The relationship between thyroid dose and diagnosis of primary hypothyroidism in pediatric brain tumor patients receiving craniospinal irradiation
- Molecular characterization of Chilean patients with a clinical diagnosis of Noonan syndrome
- Expensive therapies in children: benefit versus cost of combined treatment of recombinant human growth hormone and gonadotropin-releasing hormone analogue in girls with poor height potential
- The absence of mutations in homeobox candidate genes HOXA3, HOXB3, HOXD3 and PITX2 in familial and sporadic thyroid hemiagenesis
- A truncating DUOX2 mutation (R434X) causes severe congenital hypothyroidism
- Heterozygous GHR gene mutation in a child with idiopathic short stature
- A novel compound mutation of CYP27B1 in a Chinese family with vitamin D-dependent rickets type 1A
- A de novo mutation of DAX1 in a boy with congenital adrenal hypoplasia without hypogonadotropic hypogonadism
- Patient reports
- Hypercalcemia and osteolytic lesions as presenting symptoms of acute lymphoblastic leukemia in childhood. The use of zoledronic acid and review of the literature
- Preterm ovarian hyperstimulation syndrome presented with vaginal bleeding: a case report
- Pituitary stalk lesion in a 13-year-old female
- Radiologic manifestation of a BCS1L-mutated patient
- Permanent neonatal diabetes mellitus caused by a novel mutation in the KCNJ11 gene
- NKX2-1 mutations in brain-lung-thyroid syndrome: a case series of four patients
- A teenage boy with hypocalcemia after radioablation for Graves’ disease
- Short communication
- A common thyroid peroxidase gene mutation (G319R) in Turkish patients with congenital hypothyroidism could be due to a founder effect
- Letter to the Editor
- Endometriosis and migraine: what is there behind the scenes?
- 10.1515/jpem-2014-0999
