Download PDF
J Pediatr Genet 2015; 04(04): 194-198
DOI: 10.1055/s-0035-1565268
Original Article
Georg Thieme Verlag KG Stuttgart · New York

A Homozygous TPO Gene Duplication (c.1184_1187dup4) Causes Congenital Hypothyroidism in Three Siblings Born to a Consanguineous Family

Hakan Cangul
1   Department of Medical Genetics, Istanbul Medipol University, International School of Medicine, Istanbul, Turkey
2   Centre for Rare Diseases and Personalised Medicine, University of Birmingham, School of Clinical and Experimental Medicine, Birmingham, United Kingdom
,
Banu K. Aydin
3   Pediatric Endocrinology Unit, Istanbul Faculty of Medicine, Istanbul University, Turkey
,
Firdevs Bas
3   Pediatric Endocrinology Unit, Istanbul Faculty of Medicine, Istanbul University, Turkey
› Author Affiliations
Further Information

Publication History

18 March 2015

16 April 2015

Publication Date:
14 October 2015 (online)

    Permissions and Reprints

Abstract

Congenital hypothyroidism (CH) is the most common neonatal endocrine disease, and germ-line mutations in the TPO gene cause the inherited form of the disease. Our aim in this study was to determine the genetic basis of congenital hypothyroidism in three affected children coming from a consanguineous Turkish 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-gene by conventional sequencing. The family showed potential linkage to the TPO gene and we detected a homozygous duplication (c.1184_1187dup4) in all cases. The mutation segregated with disease status in the family. This study confirms the pathogenicity of the c.1184_1187dup4 mutation in the TPO gene and helps establish a genotype/phenotype correlation associated with this mutation. It also highlights the importance of molecular genetic studies in the definitive diagnosis and accurate classification of CH.

Keywords

TPO - mutation - genetics - duplication - congenital hypothyroidism - thyroid dyshormonogenesis
 

  • References

  • 1 Medeiros-Neto G, Knobel M, DeGroot LJ. Genetic disorders of the thyroid hormone system. In: Baxter JD, ed. Genetics in Endocrinology. Philadelphia, PA: Lippincott Williams & Wilkins; 2002: 375-402
    Google Scholar
  • 2 Park SM, Chatterjee VKK. Genetics of congenital hypothyroidism. J Med Genet 2005; 42 (5) 379-389
    CrossrefPubMedGoogle Scholar
  • 3 Castanet M, Polak M, Bonaïti-Pellié C, Lyonnet S, Czernichow P, Léger J ; AFDPHE (Association Française pour le Dépistage et la Prévention des Handicaps de l'Enfant). 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) 2009-2014
    CrossrefPubMedGoogle Scholar
  • 4 Kopp P. Perspective: genetic defects in the etiology of congenital hypothyroidism. Endocrinology 2002; 143 (6) 2019-2024
    CrossrefPubMedGoogle Scholar
  • 5 Caputo M, Rivolta CM, Esperante SA , et al. Congenital hypothyroidism with goitre caused by new mutations in the thyroglobulin gene. Clin Endocrinol (Oxf) 2007; 67 (3) 351-357
    CrossrefPubMedGoogle Scholar
  • 6 Grasberger H, Refetoff S. Genetic causes of congenital hypothyroidism due to dyshormonogenesis. Curr Opin Pediatr 2011; 23 (4) 421-428
    CrossrefPubMedGoogle Scholar
  • 7 Targovnik HM, Esperante SA, Rivolta CM. Genetics and phenomics of hypothyroidism and goiter due to thyroglobulin mutations. Mol Cell Endocrinol 2010; 322 (1–2) 44-55
    CrossrefPubMedGoogle Scholar
  • 8 Taurog A. Thyroid peroxidase and thyroxine biosynthesis. Recent Prog Horm Res 1970; 26: 189-247
    PubMedGoogle Scholar
  • 9 Kimura S, Kotani T, McBride OW , et al. Human thyroid peroxidase: complete cDNA and protein sequence, chromosome mapping, and identification of two alternately spliced mRNAs. Proc Natl Acad Sci U S A 1987; 84 (16) 5555-5559
    CrossrefPubMedGoogle 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 thyroid. Endocrinology 1991; 128 (2) 779-785
    CrossrefPubMedGoogle Scholar
  • 11 Kusakabe T. Deficient cytochrome b5 reductase activity in nontoxic goiter with iodide organification defect. Metabolism 1975; 24 (10) 1103-1113
    CrossrefPubMedGoogle 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 (2) 344-348
    CrossrefPubMedGoogle Scholar
  • 13 Figueiredo MD, Cardoso LC, Ferreira AC , 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) 4843-4848
    CrossrefPubMedGoogle Scholar
  • 14 Dupuy C, Ohayon R, Valent A, Noël-Hudson MS, Dème 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) 37265-37269
    CrossrefPubMedGoogle Scholar
  • 15 De Deken X, Wang D, Many MC , et al. Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J Biol Chem 2000; 275 (30) 23227-23233
    CrossrefPubMedGoogle Scholar
  • 16 Cangül H, Doğan M, Sağlam Y , et al. One base deletion (c.2422delT) in the TPO gene causes severe congenital hypothyroidism. J Clin Res Pediatr Endocrinol 2014; 6 (3) 169-173
    PubMedGoogle Scholar
  • 17 Cangul H, Bas VN, Saglam Y , et al. A nonsense thyrotropin receptor gene mutation (R609X) is associated with congenital hypothyroidism and heart defects. J Pediatr Endocrinol Metab 2014; 27 (11–12) 1101-1105
    PubMedGoogle Scholar
  • 18 Cangul H, Boelaert K, Dogan M , et al. Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism. Endocrine 2014; 45 (2) 206-212
    CrossrefPubMedGoogle Scholar
  • 19 Cangul H, Aycan Z, Kendall M , et al. A truncating DUOX2 mutation (R434X) causes severe congenital hypothyroidism. J Pediatr Endocrinol Metab 2014; 27 (3–4) 323-327
    PubMedGoogle Scholar
  • 20 Baş VN, Aycan Z, Cangul H , et al. A common thyroid peroxidase gene mutation (G319R) in Turkish patients with congenital hypothyroidism could be due to a founder effect. J Pediatr Endocrinol Metab 2014; 27 (34) 383-387
    PubMedGoogle Scholar
  • 21 Schoenmakers NA, Cangul H, Nicholas A , et al. A comprehensive next generation sequencing-based strategy for genetic diagnosis in congenital hypothyroidism. Endocrine Abstracts. doi: 10.1530/endoabs.33.OC2.9
    PubMedGoogle Scholar
  • 22 Cangul H, Aycan Z, Olivera-Nappa A , et al. Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community. Clin Endocrinol (Oxf) 2013; 79 (2) 275-281
    CrossrefPubMedGoogle Scholar
  • 23 Cangul H, Morgan NV, Forman JR , et al. Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism. Clin Endocrinol (Oxf) 2010; 73 (5) 671-677
    CrossrefPubMedGoogle Scholar
  • 24 Cangul H, Saglam H, Aycan Z , et al. Locus heterogeneity and mutations in thyrotropin receptor gene in autosomal recessively inherited congenital hypothyroidism. J Med Genet 2010; 1: S59
    PubMedGoogle Scholar
  • 25 Cangul H, Morgan NV, Pasha S , et al. Genetic heterogeneity in congenital hypothyroidism. J Med Genet 2009; 1: S74
    PubMedGoogle Scholar
  • 26 Cangul H, Darendeliler F, Saglam Y , et al. A truncating TPO mutation (Y55X) in patients with hypothyroidism and total iodide organification defect. Endocr Res 2015; 40 (3) 146-150
    CrossrefPubMedGoogle Scholar
  • 27 Abramowicz MJ, Vassart G, Christophe D. Thyroid peroxidase gene promoter confers TSH responsiveness to heterologous reporter genes in transfection experiments. Biochem Biophys Res Commun 1990; 166 (3) 1257-1264
    CrossrefPubMedGoogle Scholar
  • 28 Shyu AB, Wilkinson MF, van Hoof A. Messenger RNA regulation: to translate or to degrade. EMBO J 2008; 27 (3) 471-481
    CrossrefPubMedGoogle Scholar
  • 29 Abramowicz MJ, Targovnik HM, Varela V , 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) 1200-1204
    CrossrefPubMedGoogle Scholar