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Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis

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Abstract

Purpose

Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 17 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH).

Methods

Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO), Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), DUOX2, Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants.

Results

Four novel variants have been identified, two in TPO: c.2749-2 A > C and c.2752_2753delAG, [p.Ser918Cysfs*62] and two variants in DUOX2 gene: c.425 C > G [p.Pro142Arg] and c.2695delC [p.Gln899Serfs*21]. Eighteen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic biallelic variants in TPO and DUOX2 in 7 and 2 patients, respectively. We also detected a potentially pathogenic monoallelic variant in TPO and DUOX2 in 7 and 1 patients respectively.

Conclusions

22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.

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Data availability

Data and material are available from the authors upon request.

References

  1. M.J. Kwak, Clinical genetics of defects in thyroid hormone synthesis. Ann. Pediatr. Endocrinol. Metab. 23, 169–175 (2018). https://doi.org/10.6065/apem.2018.23.4.169

    Article  PubMed  PubMed Central  Google Scholar 

  2. A. Stoupa, D. Kariyawasam, M. Muzza, T. de Filippis, L. Fugazzola, M. Polak, L. Persani, A. Carré, New genetics in congenital hypothyroidism. Endocrine 71, 696–705 (2021). https://doi.org/10.1007/s12020-021-02646-9

    Article  CAS  PubMed  Google Scholar 

  3. P. van Trotsenburg, A. Stoupa, J. Léger, T. Rohrer, C. Peters, L. Fugazzola, A. Cassio, C. Heinrichs, V. Beauloye, J. Pohlenz, P. Rodien, R. Coutant, G. Szinnai, P. Murray, B. Bartés, D. Luton, M. Salerno, L. de Sanctis, M. Vigone, H. Krude, L. Persani, M. Polak, Congenital hypothyroidism: a 2020-2021 consensus guidelines update-an ENDO-European reference network initiative endorsed by the European society for pediatric endocrinology and the European society for endocrinology. Thyroid 31, 387–419 (2021). https://doi.org/10.1089/thy.2020.0333

    Article  PubMed  PubMed Central  Google Scholar 

  4. H.M. Targovnik, K.G. Scheps, C.M. Rivolta, Defects in protein folding in congenital hypothyroidism. Mol. Cell. Endocrinol. 501, 110638 (2020). https://doi.org/10.1016/j.mce.2019.110638

    Article  CAS  PubMed  Google Scholar 

  5. F. Wang, Y. Zang, M. Li, W. Liu, Y. Wang, X. Yu, H. Li, F. Wang, S. Liu, DUOX2 and DUOXA2 variants confer susceptibility to thyroid dysgenesis and gland-in-situ with congenital hypothyroidism. Front. Endocrinol. (Lausanne) 11, 237 (2020). https://doi.org/10.3389/fendo.2020.00237

    Article  Google Scholar 

  6. J.C. Moreno, H. Bikker, M.J.E. Kempers, A.S.P. van Trotsenburg, F. Baas, J.J.M. de Vijlder, T. Vulsma, C. Ris-Stalpers, Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N. Engl. J. Med. 347, 95–102 (2002). https://doi.org/10.1056/NEJMoa012752

    Article  CAS  PubMed  Google Scholar 

  7. C.M. Rivolta, S.A. Esperante, L. Gruñeiro-Papendieck, A. Chiesa, C.M. Moya, S. Domené, V. Varela, H.M. Targovnik, Five novel inactivating mutations in the human thyroid peroxidase gene responsible for congenital goiter and iodide organification defect. Hum. Mutat. 22, 259 (2003). https://doi.org/10.1002/humu.9175

    Article  PubMed  Google Scholar 

  8. S. Richards, N. Aziz, S. Bale, D. Bick, S. Das, J. Gastier-Foster, W.W. Grody, M. Hegde, E. Lyon, E. Spector, K. Voelkerding, H.L. Rehm; ACMG Laboratory Quality Assurance Committee, Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015). https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  9. H. Bikker, F. Baas, J.J.M. de Vijlder, Molecular analysis of mutated thyroid peroxidase detected in patients with total iodide organification defects. J. Clin. Endocrinol. Metab. 82, 649–653 (1997). https://doi.org/10.1210/jcem.82.2.3729

    Article  CAS  PubMed  Google Scholar 

  10. F.S. Belforte, A.M. Targovnik, R.M. González-Lebrero, C. Osorio Larroche, C.E. Citterio, R. González-Sarmiento, M.V. Miranda, H.M. Targovnik, C.M. Rivolta, Kinetic characterization of human thyroperoxidase. Normal and pathological enzyme expression in Baculovirus system: a molecular model of functional expression. Mol. Cell. Endocrinol. 404, 9–15 (2015). https://doi.org/10.1016/j.mce.2014.12.026

    Article  CAS  PubMed  Google Scholar 

  11. R.-J. Zhang, F. Sun, F. Chen, Y. Fang, C.-Y. Yan, C.-R. Zhang, Y.-X. Ying, Z. Wang, C.-X. Zhang, F.-Y. Wu, B. Han, J. Liang, S.-X. Zhao, H.-D. Song, The TPO mutation screening and genotype-phenotype analysis in 230 Chinese patients with congenital hypothyroidism. Mol. Cell. Endocrinol. 506, 110761 (2020). https://doi.org/10.1016/j.mce.2020.110761

    Article  CAS  PubMed  Google Scholar 

  12. M. Muzza, S. Rabbiosi, M.C. Vigone, I. Zamproni, V. Cirello, M.A. Maffini, K. Maruca, N. Schoenmakers, L. Beccaria, F. Gallo, S.-M. Park, P. Beck-Peccoz, L. Persani, G. Weber, L. Fugazzola, The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects. J. Clin. Endocrinol. Metab. 99, E544–E553 (2014). https://doi.org/10.1210/jc.2013-3618

    Article  CAS  PubMed  Google Scholar 

  13. M.V. Rastogi, S.H. LaFranchi, Congenital hypothyroidism Orphanet. J. Rare Dis. 5, 17 (2010). https://doi.org/10.1186/1750-1172-5-17

    Article  Google Scholar 

  14. A. Stoupa, R. Chaabane, M. Guériouz, C. Raynaud-Ravni, P. Nitschke, C. Bole-Feysot, M. Mnif, L. Ammar Keskes, M. Hachicha, N. Belguith, M. Polak, A. Carré, Thyroid hypoplasia in congenital hypothyroidism associated with thyroid peroxidase mutations. Thyroid 28, 941–944 (2018). https://doi.org/10.1089/thy.2017.0502

    Article  CAS  PubMed  Google Scholar 

  15. P. Srichomkwun, J. Takamatsu, D.A. Nickerson, M.J. Bamshad, J.X. Chong, S. Refetoff, DUOX2 gene mutation manifesting as resistance to thyrotropin phenotype. Thyroid 27, 129–131 (2017). https://doi.org/10.1089/thy.2016.0469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. C. Fu, B. Xie, S. Zhang, J. Wang, S. Luo, H. Zheng, J. Su, X. Hu, R. Chen, X. Fan, J. Luo, X. Gu, S. Chen, Mutation screening of the TPO gene in a cohort of 192 Chinese patients with congenital hypothyroidism. BMJ Open 6, e010719 (2016). https://doi.org/10.1136/bmjopen-2015-010719

    Article  PubMed  PubMed Central  Google Scholar 

  17. G. De Marco, P. Agretti, L. Montanelli, C. Di Cosmo, B. Bagattini, M. De Servi, E. Ferrarini, A. Dimida, A.C. Freitas Ferreira, A. Molinaro, C. Ceccarelli, F. Brozzi, A. Pinchera, P. Vitti, M. Tonacchera, Identification and functional analysis of novel dual oxidase 2 (DUOX2) mutations in children with congenital or subclinical hypothyroidism. J. Clin. Endocrinol. Metab. 96, E1335–E1339 (2011). https://doi.org/10.1210/jc.2010-2467

    Article  CAS  PubMed  Google Scholar 

  18. F. Wang, K. Lu, Z. Yang, S. Zhang, W. Lu, L. Zhang, S. Liu, S. Yan, Genotypes and phenotypes of congenital goitre and hypothyroidism caused by mutations in dual oxidase 2 genes. Clin. Endocrinol. (Oxf.) 81, 452–457 (2014). https://doi.org/10.1111/cen.12469

    Article  CAS  Google Scholar 

  19. C. Peters, A.K. Nicholas, E. Schoenmakers, G. Lyons, S. Langham, E.G. Serra, N.J. Sebire, M. Muzza, L. Fugazzola, N. Schoenmakers, DUOX2/DUOXA2 mutations frequently cause congenital hypothyroidism that evades detection on newborn screening in the United Kingdom. Thyroid 29, 790–801 (2019). https://doi.org/10.1089/thy.2018.0587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. M. Tan, Y. Huang, X. Jiang, P. Li, C. Tang, X. Jia, Q. Chen, W. Chen, H. Sheng, Y. Feng, D. Wu, L. Liu, The prevalence, clinical, and molecular characteristics of congenital hypothyroidism caused by DUOX2 mutations: a population-based cohort study in Guangzhou. Horm. Metab. Res. 48, 581–588 (2016). https://doi.org/10.1055/s-0042-112224

    Article  CAS  PubMed  Google Scholar 

  21. X. Fan, C. Fu, Y. Shen, C. Li, S. Luo, Q. Li, J. Luo, J. Su, S. Zhang, X. Hu, R. Chen, X. Gu, S. Chen, Next-generation sequencing analysis of twelve known causative genes in congenital hypothyroidism. Clin. Chim. Acta 468, 76–80 (2017). https://doi.org/10.1016/j.cca.2017.02.009

    Article  CAS  PubMed  Google Scholar 

  22. S. Liu, W. Han, Y. Zang, H. Zang, F. Wang, P. Jiang, H. Wei, X. Liu, Y. Wang, X. Ma, Y. Ge, Identification of two missense mutations in DUOX1 (p.R1307Q) and DUOXA1 (p.R56W) that can cause congenital hypothyroidism through impairing H2O2 generation. Front. Endocrinol. (Lausanne) 10, 526 (2019). https://doi.org/10.3389/fendo.2019.00526

    Article  Google Scholar 

  23. H. Cangul, X.-H. Liao, E. Schoenmakers, J. Kero, S. Barone, P. Srichomkwun, H. Iwayama, E.G. Serra, H. Saglam, E. Eren, O. Tarim, A.K. Nicholas, I. Zvetkova, C.A. Anderson, F.E.K. Frankl, K. Boelaert, M. Ojaniemi, J. Jääskeläinen, K. Patyra, C. Löf, E.D. Williams; UK10K Consortium, M. Soleimani, T. Barrett, E.R. Maher, V.K. Chatterjee, S. Refetoff, N. Schoenmakers, Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism. JCI insight 3, e99631 (2018). https://doi.org/10.1172/jci.insight.99631

    Article  PubMed Central  Google Scholar 

  24. X. De Deken, F. Miot, DUOX defects and their roles in congenital hypothyroidism. In: Knaus U.G., T. L. Leto (eds.) NADPH Oxidases: Methods and Protocols, Methods in Molecular Biology, vol. 1982, 667-693. Springer Science+Business Media

  25. T. de Filippis, G. Gelmini, E. Paraboschi, M.C. Vigone, M. di Frenna, F. Marelli, M. Bonomi, A. Cassio, D. Larizza, M. Moro, G. Radetti, M. Salerno, D. Ardissino, G. Weber, D. Gentilini, F. Guizzardi, S. Duga, L. Persani, A frequent oligogenic involvement in congenital hypothyroidism. Hum. Mol. Genet. 26, 2507–2514 (2017). https://doi.org/10.1093/hmg/ddx145

    Article  CAS  PubMed  Google Scholar 

  26. W. Long, G. Lu, W. Zhou, Y. Yang, B. Zhang, H. Zhou, L. Jiang, B. Yu, Targeted next-generation sequencing of thirteen causative genes in Chinese patients with congenital hypothyroidism. Endocr. J. 65, 1019–1028 (2018). https://doi.org/10.1507/endocrj.EJ18-0156

    Article  CAS  PubMed  Google Scholar 

  27. S.-G. Ma, X. Zheng, Y.-L. Qiu, M.-L. Guo, X.-J. Shao, Compound heterozygous mutations (p.T561M and c.2422delT) in the TPO gene associated with congenital hypothyroidism. J. Pediatr. Endocrinol. Metab. 29, 567–570 (2016). https://doi.org/10.1515/jpem-2015-0383

    Article  CAS  PubMed  Google Scholar 

  28. M.J. Abramowicz, H.M. Targovnik, V. Varela, P. Cochaux, L. Krawiec, M.A. Pisarev, F.V.E. Propato, G. Juvenal, H.A. Chester, G. Vassart, Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter. J. Clin. Invest. 90, 1200–1204 (1992). https://doi.org/10.1172/JCI115981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. A. Grüters, B. Köhler, A. Wolf, A. Söling, L. de Vijlder, H. Krude, H. Biebermann, Screening for mutations of the human thyroid peroxidase gene in patients with congenital hypothyroidism. Exp. Clin. Endocrinol. Diabetes 104, 121–123 (1996). https://doi.org/10.1055/s-0029-1211718

    Article  PubMed  Google Scholar 

  30. C.L.S. Santos, H. Bikker, K.G.M. Rego, A.C. Nascimento, M. Tambascia, J.J.M. de Vijlder, G. Medeiros-Neto, A novel mutation in the TPO gene in goitrous hypothyroid patients with iodide organification defect. Clin. Endocrinol. (Oxf.) 51, 165–172 (1999). https://doi.org/10.1046/j.1365-2265.1999.00746.x

    Article  CAS  Google Scholar 

  31. B. Bakker, H. Bikker, T. Vulsma, J.S.E. de Randamie, B.M. Wiedijk, J.J.M. de Vijlder, Two decades of screening for congenital hypothyroidism in the Netherlands: TPO gene mutations in total iodide organification defect (an update). J. Clin. Endocrinol. Metab. 85, 3708–3712 (2000). https://doi.org/10.1210/jcem.85.10.6878

    Article  CAS  PubMed  Google Scholar 

  32. F. Calaciura, G. Miscio, A. Coco, D. Leonardi, C. Cisternino, C. Regalbuto, M. Bozzali, R. Maiorana, A. Ranieri, A. Carta, M. Buscema, V. Trischitta, L. Sava, V. Tassi, Genetics of specific phenotypes of congenital hypothyroidism: a population-based approach. Thyroid 12, 945–951 (2002). https://doi.org/10.1089/105072502320908277

    Article  CAS  PubMed  Google Scholar 

  33. A.C. Nascimento, D.R. Guedes, C.S. Santos, M. Knobel, I.G.S. Rubio, G. Medeiros-Neto, Thyroperoxidase gene mutations in congenital goitrous hypothyroidism with total and partial iodide organification defect. Thyroid 13, 1145–1151 (2003). https://doi.org/10.1089/10507250360731550

    Article  CAS  PubMed  Google Scholar 

  34. L. Fugazzola, D. Mannavola, M.C. Vigone, V. Cirello, G. Weber, P. Beck-Peccoz, L. Persani, Total iodide organification defect: clinical and molecular characterization of an Italian family. Thyroid 15, 1085–1088 (2005). https://doi.org/10.1089/thy.2005.15.1085

    Article  CAS  PubMed  Google Scholar 

  35. C. Rodrigues, P. Jorge, J.P. Soares, I. Santos, R. Salomão, M. Madeira, R.V. Osório, R. Santos, Mutation screening of the thyroid peroxidase gene in a cohort of 55 Portuguese patients with congenital hypothyroidism. Eur. J. Endocrinol. 152, 193–198 (2005). https://doi.org/10.1530/eje.1.01826

    Article  CAS  PubMed  Google Scholar 

  36. M. Avbelj, H. Tahirovic, M. Debeljak, M. Kusekova, A. Toromanovic, C. Krzisnik, T. Battelino, High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis. Eur. J. Endocrinol. 156, 511–519 (2007). https://doi.org/10.1530/EJE-07-0037

    Article  CAS  PubMed  Google Scholar 

  37. F.S. Belforte, M.B. Miras, M.C. Olcese, G. Sobrero, G. Testa, L. Muñoz, L. Gruñeiro-Papendieck, A. Chiesa, R. González-Sarmiento, H.M. Targovnik, C.M. Rivolta, Congenital goitrous hypothyroidism: mutation analysis in the thyroid peroxidase gene. Clin. Endocrinol. (Oxf.) 76, 568–576 (2012). https://doi.org/10.1111/j.1365-2265.2011.04249.x

    Article  CAS  Google Scholar 

  38. K. Altmann, P. Hermanns, R. Mühlenberg, S. Fricke-Otto, R. Wentzell, J. Pohlenz, Congenital goitrous primary hypothyroidism in two German families caused by novel thyroid peroxidase (TPO) gene mutations. Exp. Clin. Endocrinol. Diabetes 121, 343–346 (2013). https://doi.org/10.1055/s-0033-1333766

    Article  CAS  PubMed  Google Scholar 

  39. H. Cangul, Z. Aycan, A. Olivera-Nappa, H. Saglam, N.A. Schoenmakers, K. Boelaert, S. Cetinkaya, O. Tarim, E. Bober, F. Darendeliler, V. Bas, K. Demir, B.K. Aydin, M. Kendall, T. Cole, W. Högler, V.K.K. Chatterjee, T.G. Barrett, E.R. Maher, Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community. Clin. Endocrinol. (Oxf.) 79, 275–281 (2013). https://doi.org/10.1111/cen.12127

    Article  CAS  Google Scholar 

  40. H. Cangul, B.K. Aydin, F. Bas, A homozygous TPO gene duplication (c.1184_1187dup4) causes congenital hypothyroidism in three siblings born to a consanguineous family. J. Pediatr. Genet. 4, 194–198 (2015). https://doi.org/10.1055/s-0035-1565268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. C. Löf, K. Patyra, T. Kuulasmaa, J. Vangipurapu, H. Undeutsch, H. Jaeschke, T. Pajunen, A. Kero, H. Krude, H. Biebermann, G. Kleinau, P. Kühnen, K. Rantakari, P. Miettinen, T. Kirjavainen, J.-P. Pursiheimo, T. Mustila, J. Jääskeläinen, M. Ojaniemi, J. Toppari, J. Ignatius, M. Laakso, J. Kero, Detection of novel gene variants associated with congenital hypothyroidism in a Finnish patient cohort. Thyroid 26, 1215–1224 (2016). https://doi.org/10.1089/thy.2016.0016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. A.K. Nicholas, E.G. Serra, H. Cangul, S. Alyaarubi, I. Ullah, E. Schoenmakers, A. Deeb, A.M. Habeb, M. Almaghamsi, C. Peters, N. Nathwani, Z. Aycan, H. Saglam, E. Bober, M. Dattani, S. Shenoy, P.G. Murray, A. Babiker, R. Willemsen, A. Thankamony, G. Lyons, R. Irwin, R. Padidela, K. Tharian, J.H. Davies, V. Puthi, S.-M. Park, A.F. Massoud, J.W. Gregory, A. Albanese, E. Pease-Gevers, H. Martin, K. Brugger, E.R. Maher, V.K.K. Chatterjee, C.A. Anderson, N. Schoenmakers, Comprehensive screening of eight causatives genes in congenital hypothyroidism with gland-in-situ. J. Clin. Endocrinol. Metab. 101, 4521–4531 (2016). https://doi.org/10.1210/jc.2016-1879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. N. Makretskaya, O. Bezlepkina, A. Kolodkina, A. Kiyaev, E.V. Vasilyev, V. Petrov, S. Kalinenkova, O. Malievsky, I.I. Dedov, A. Tiulpakov, High frequency of mutations in ‘dyshormonogenesis genes’ in severe congenital hypothyroidism. Plos One 13, e0204323 (2018). https://doi.org/10.1371/journal.pone.0204323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. M. Zou, A.S. Alzahrani, A. Al-Odaib, M.A. Alqahtani, O. Babiker, R.A. Al-Rijjal, H.A. BinEssa, W.E. Kattan, A.F. Al-Enezi, A. Al Qarni, M.S.A. Al-Faham, E.Y. Baitei, A. Alsagheir, B.F. Meyer, Y. Shi, Molecular analysis of congenital hypothyroidism in Saudi Arabia: SLC26A7 mutation is a novel defect in thyroid dyshormonogenesis. J. Clin. Endocrinol. Metab. 103, 1889–1898 (2018). https://doi.org/10.1210/jc.2017-02202

    Article  PubMed  Google Scholar 

  45. R. Santos-Silva, M. Rosário, A. Grangeia, C. Costa, C. Castro-Correia, I. Alonso, M. Leão, M. Fontoura, Genetic analyses in a cohort of Portuguese pediatric patients with congenital hypothyroidism. J. Pediatr. Endocrinol. Metab. 32, 1265–1273 (2019). https://doi.org/10.1515/jpem-2019-0047

    Article  CAS  PubMed  Google Scholar 

  46. S. Guria, B. Bankura, N. Balmiki, A.K. Pattanayak, T.K. Das, A. Sinha, S. Chakrabarti, S. Chowdhury, M. Das, Functional analysis of thyroid peroxidase gene mutations detected in patients with thyroid dyshormonogenesis. Int. J. Endocrinol. 2014, 390121 (2014). https://doi.org/10.1155/2014/390121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. M.N. Begum, M.T. Islam, S.R. Hossain, G.S. Bhuyan, M.A. Halim, I. Shahriar, S.K. Sarker, S. Haque, T.K. Konika, M.S. Islam, A. Rahat, S.K. Qadri, R. Sultana, S. Begum, S. Sultana, N. Saha, M. Hasan, M.A. Hasanat, H. Banu, H.U. Shekhar, E.K. Chowdhury, A.A. Sajib, A.B.M.M.K. Islam, S.S. Qadri, F. Qadri, S. Akhteruzzaman, K. Mannoor, Mutation spectrum in TPO gene of Bangladeshi patients with thyroid dyshormonogenesis and analysis of the effects of different mutations on the structural features and functions of TPO protein through in silico approach. Biomed. Res. Int. 2019, 9218903 (2019). https://doi.org/10.1155/2019/9218903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. S. Pannain, R.E. Weiss, C.E. Jackson, D. Dian, J.C. Beck, V.C. Sheffield, N. Cox, S. Refetoff, Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping. J. Clin. Endocrinol. Metab. 84, 1061–1071 (1999). https://doi.org/10.1210/jcem.84.3.5541

    Article  CAS  PubMed  Google Scholar 

  49. Y. Maruo, K. Nagasaki, K. Matsui, Y. Mimura, A. Mori, M. Fukami, Y. Takeuchi, Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty. Eur. J. Endocrinol. 174, 453–463 (2016). https://doi.org/10.1530/EJE-15-0959

    Article  CAS  PubMed  Google Scholar 

  50. V. Varela, C.M. Rivolta, S.A. Esperante, L. Gruñeiro-Papendieck, A. Chiesa, H.M. Targovnik, 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. 52, 182–191 (2006). https://doi.org/10.1373/clinchem.2005.058321

    Article  CAS  PubMed  Google Scholar 

  51. K. Sorapipatcharoen, T. Tim-Aroon, P. Mahachoklertwattana, W. Chantratita, N. Iemwimangsa, I. Sensorn, B. Panthan, P. Jiaranai, S. Noojarern, P. Khlairit, S. Pongratanakul, C. Suprasongsin, M. Korwutthikulrangsri, C. Sriphrapradang, P. Poomthavorn, DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients. Endocr. Connect. 9, 1121–1134 (2020). https://doi.org/10.1530/EC-20-0411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. I. Oliver-Petit, T. Edouard, V. Jacques, M. Bournez, A. Cartault, S. Grunenwald, F. Savagner, Next-generation sequencing analysis reveals frequent familial origin and oligogenism in congenital hypothyroidism with dyshormonogenesis. Front. Endocrinol. (Lausanne) 12, 657913 (2021). https://doi.org/10.3389/fendo.2021.657913

    Article  Google Scholar 

  53. J. Deladoëy, N. Pfarr, J.-M. Vuissoz, J. Parma, G. Vassart, S. Biesterfeld, J. Pohlenz, G. van Vliet, Pseudodominant inheritance of goitrous congenital hypothyroidism caused by TPO mutations: molecular and in silico studies. J. Clin. Endocrinol. Metab. 93, 627–633 (2008). https://doi.org/10.1210/jc.2007-2276

    Article  CAS  PubMed  Google Scholar 

  54. A.H.M. AL-Faisal, I.J. AL-Ramahi, I.A. Abudl-Hassan, A.T. Hamdan, S. Barusrux, Detection of heterozygous c.1708C>T and c.1978C>G thyroid peroxidase (TPO) mutations in Iraqi patients with toxic and nontoxic goiter. Comp. Clin. Pathol. 23, 69–75 (2014). https://doi.org/10.1007/s00580-012-1572-9

    Article  CAS  Google Scholar 

  55. K. Umeki, T. Kotani, J.-I. Kawano, T. Suganuma, I. Yamamoto, Y. Aratake, M. Furujo, Y. Ichiba, Two novel missense mutations in the thyroid peroxidase gene, R665W and G771R, result in a localization defect and cause congenital hypothyroidism. Eur. J. Endocrinol. 146, 491–498 (2002). https://doi.org/10.1530/eje.0.1460491

    Article  CAS  PubMed  Google Scholar 

  56. C.M. Figueiredo, I. Falcão, J. Vilaverde, J. Freitas, M.J. Oliveira, C. Godinho, J. Dores, M.C. Rodrigues, C. Carvalho, T. Borges, Prenatal diagnosis and management of a fetal goiter hypothyroidism due to dyshormonogenesis. Case Rep. Endocrinol. 2018, 9564737 (2018). https://doi.org/10.1155/2018/9564737

    Article  PubMed  PubMed Central  Google Scholar 

  57. D. Zhao, Y. Li, Z. Shan, W. Teng, J. Li, X. Teng, Functional analysis of thyroid peroxidase gene mutations resulting in congenital hypothyroidism. Clin. Endocrinol. (Oxf.) 93, 499–507 (2020). https://doi.org/10.1111/cen.14253

    Article  CAS  Google Scholar 

  58. T. Kotani, K. Umeki, I. Yamamoto, H. Maesaka, K. Tachibana, S. Ohtaki, A novel mutation in the human thyroid peroxidase gene resulting in a total iodide organification defect. J. Endocrinol. 160, 267–273 (1999). https://doi.org/10.1677/joe.0.1600267

    Article  CAS  PubMed  Google Scholar 

  59. S.-T. Lee, D.H. Lee, J.-Y. Kim, M.-J. Kwon, J.-W. Kim, Y.-H. Hong, Y.-W. Lee, C.-S. Ki, Molecular screening of the TSH receptor (TSHR) and thyroid peroxidase (TPO) genes in Korean patients with nonsyndromic congenital hypothyroidism. Clin. Endocrinol. 75, 715–721 (2011). https://doi.org/10.1111/j.1365-2265.2011.04156.x

    Article  CAS  Google Scholar 

  60. M.M.L. Kizys, R.A. Louzada, M. Mitne-Neto, J.R. Jara, G.K. Furuzawa, D.P. de Carvalho, M.R. Dias-da-Silva, S. Nesi-França, C. Dupuy, R.M.B. Maciel, DUOX2 mutations are associated with congenital hypothyroidism with ectopic thyroid gland. J. Clin. Endocrinol. Metab. 102, 4060–4071 (2017). https://doi.org/10.1210/jc.2017-00832

    Article  PubMed  Google Scholar 

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Acknowledgements

M.F.M. and M.G.P. are research fellows of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). F.S.B., A.C., H.M.T., and C.M.R. are established investigators of the CONICET.

Author contributions:

M.F.M., F.S.B., E.B.M., E.A., M.C.O., M.G.P., H.M.T. and C.M.R. conducted experiments, specifically, M.F.M. contributed to performing Sanger sequencing, structural modeling analysis and checking references, F.S.B. contributed to performing Sanger sequencing, E.B.M. and C.M.R. contributed to performing and analyzing Next-Generation Sequencing, E.A. contributes with technical assistance of the experimental protocols, M.C.O. contributed to performing structural modeling protocols, M.G.P. and H.M.T. contributed to performing bioinformatic prediction tools. P.P., G.S., V.A.B., A.C., M.B.M. and V.G.G. were involved in the recruitment of patients and acquisition of clinical data and blood samples. R.G.-S. contributed to the acquisition of funds and the design of the study. H.M.T. and C.M.R. contributed to the acquisition of funds, the conception and design of the study and they contributed to the writing of the paper. C.M.R. is the study chief investigator. All authors critically reviewed and participated in manuscript revision and approved the final draft.

Funding

This study was funded by grants from the Fondo para la Investigación Científica y Tecnológica (FONCyT-ANPCyT-MINCyT, PICT 2014-1193 to CMR, PICT 2015-1811 and PICT-2018-02146 to H.M.T.), CONICET (PIP 2015-11220150100499 to C.M.R.), Universidad de Buenos Aires (UBACyT 2016-20020150100099BA and 2020-20020190100050BA to C.M.R.) and Fondo de Investigación Sanitaria/FEDER (PI16/01920 and PI20/01589 to R.G.-S.).

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Authors and Affiliations

  1. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología, Biotecnología y Genética/Cátedra de Genética, Universidad de Buenos Aires, Buenos Aires, Argentina

    Maricel F. Molina, Fiorella S. Belforte, Ezequiela Adrover, María C. Olcese, Mauricio Gomes Pio, Héctor M. Targovnik & Carina M. Rivolta

  2. Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina

    Maricel F. Molina, Fiorella S. Belforte, Ezequiela Adrover, María C. Olcese, Mauricio Gomes Pio, Héctor M. Targovnik & Carina M. Rivolta

  3. Centro de Investigaciones Endocrinológicas, CEDIE-CONICET, División Endocrinología, Hospital de Niños “Ricardo Gutiérrez”, Buenos Aires, Argentina

    Patricia Papendieck & Ana Chiesa

  4. Servicio de Endocrinología, Hospital de Niños Santísima Trinidad, Córdoba, Argentina

    Gabriela Sobrero & Mirta B. Miras

  5. Servicio de Endocrinología, Hospital de Niños “Sor María Ludovica”, La Plata, Argentina

    Viviana A. Balbi & Verónica G. González

  6. Unidad de Medicina Molecular-Departamento de Medicina, IBMCC and IBSAL, Universidad de Salamanca-CSIC, Salamanca, España

    Elena Bueno Martínez & Rogelio González-Sarmiento

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  1. Maricel F. Molina
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  2. Patricia Papendieck
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Corresponding author

Correspondence to Carina M. Rivolta.

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The studies involving human participants were reviewed and approved by the Ethical Committee of the Faculty of Pharmacy and Biochemistry of the University of Buenos Aires (CEIC-FFyB, No. 1094). Written informed consent was obtained from the parents of the children involved in this study.

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Molina, M.F., Papendieck, P., Sobrero, G. et al. Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis. Endocrine 77, 86–101 (2022). https://doi.org/10.1007/s12020-022-03054-3

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