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Thyroid dysgenesis: molecular analysis and functional studies of mutations in candidate genes discovered by next generation sequence in a cohort of 268 cases

Grant number: 12/01628-0
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): June 01, 2012
Effective date (End): June 08, 2016
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Rui Monteiro de Barros Maciel
Grantee:Marina Malta Letro Kizys Polisel
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated scholarship(s):14/15948-2 - Congenital hypothyroidism: in vivo functional validation of the new candidate-gene CCDC for thyroid hemiagenesis, BE.EP.DD


Congenital Hypothyroidism (CH) is the most common disorder of the endocrine system among newborns. The global incidence of CH is 1/3000-4000 births [1]. CH is mainly caused by developmental defects on thyroid, collectively known as Thyroid Dysgenesis (TDs). It is believed that the major causes of TDs result from impaired specification, proliferation or survival of thyroid precursor cells, while there is a loss of organized movement of these cells in a distinct spatiotemporal pattern. Thyroid development is under control of a combined expression of a set of transcription factors such as: Nkx2.1, Foxe1, Pax8 and Hhex.In a previous TD project, we had searched for mutations in these genes-related to embryogenesis of the thyroid gland Nkx2-1, Pax8, Foxe1, Nkx2-5, besides TSH receptor, TSHr, from the former cohort of children from "Programa de rastreamento do hipotirodismo congenito do estado do Paraná" (FAPESP 2006/54950-6). We have demonstrated that the prevalence of permanent CH is 1:4795, and the ectopic thyroid gland is the most frequent CH cause (37%), followed by dyshormonogenesis (28%), agenesis (24%), hypoplasia (10%) and hemiagenesis (1%). In the molecular analysis, we have identified mutations already reported in PAX8 and TSH-r genes, and new mutations in NKX2.5 gene [57]. Since this study, new genes have been described on thyroid gland development; some of them already studied in animal models, and related to a possible DT pathogenesis, such as HAND2, ISL1, TBX1, HOXA3, HOXB3, HOXD3, EYA1 and HHEX. So, the aim of this project is to expand the panel of candidate-genes responsible for DTs in the same cohort of children, however, including new cases from two other Thyroid Ambulatories (Adult and Pediatric Endocrinology) of EPM/UNIFESP with hypoplasia and hemiagenesis. Thereafter, we will proceed with mutation screening in these new genes related to thyroid gland embryogenesis and its functional analyses, when a mutation is present. We will go on initially with the functional analyses of mutations already found in NKX2.5 transcription factor. In a second step, we will perform the whole exome sequencing to identify new mutations in other genes initially not related to TDs in animal models. (AU)

Scientific publications (7)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
RADONSKY, VANESSA; KIZYS, MARINA MALTA LETRO; DOTTO, RENATA PIRES; ESPER, PRISCILA LIGEIRO GONCALVES; HEILBERG, ITA PFEFERMAN; DIAS-DA-SILVA, MAGNUS REGIOS; LAZARETTI-CASTRO, MARISE. Hypomagnesemia with Hypercalciuria Leading to Nephrocalcinosis, Amelogenesis Imperfecta, and Short Stature in a Child Carrying a Homozygous Deletion in theCLDN16Gene. CALCIFIED TISSUE INTERNATIONAL, v. 107, n. 4 JUL 2020. Web of Science Citations: 0.
KIZYS, MARINA M. L.; LOUZADA, RUY A.; MITNE-NETO, MIGUEL; JARA, JESSICA R.; FURUZAWA, GILBERTO K.; DE CARVALHO, DENISE P.; DIAS-DA-SILVA, MAGNUS R.; NESI-FRANCA, SUZANA; DUPUY, CORINNE; MACIEL, RUI M. B. DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v. 102, n. 11, p. 4060-4071, NOV 1 2017. Web of Science Citations: 15.
MELO, MARIA CLARA C.; DE SOUZA, JANAINA S.; KIZYS, MARINA M. L.; VIDI, ANGELA C.; DORTA, HARON S.; KUNII, ILDA S.; GIANNOCCO, GISELE; CARVALHEIRA, GIANNA; DIAS-DA-SILVA, MAGNUS R. Novel lincRNA Susceptibility Gene and Its Role in Etiopathogenesis of Thyrotoxic Periodic Paralysis. JOURNAL OF THE ENDOCRINE SOCIETY, v. 1, n. 7, p. 809-815, JUL 1 2017. Web of Science Citations: 0.
DE SOUZA, JANAINA SENA; LETRO KIZYS, MARINA MALTA; DA CONCEICAO, RODRIGO RODRIGUES; GLEBOCKI, GABRIEL; ROMANO, RENATA MARINO; ORTIGA-CARVALHO, TANIA MARIA; GIANNOCCO, GISELE; COTRIM GUERREIRO DA SILVA, ISMAEL DALE; DIAS DA SILVA, MAGNUS REGIOS; ROMANO, MARCO AURELIO; CHIAMOLERA, MARIA IZABEL. Perinatal exposure to glyphosate-based herbicide alters the thyrotrophic axis and causes thyroid hormone homeostasis imbalance in male rats. Toxicology, v. 377, p. 25-37, FEB 15 2017. Web of Science Citations: 22.
SIVIERO-MIACHON, ADRIANA A.; KIZYS, MARINA M. L.; RIBEIRO, MANUELA M.; GARCIA, FABIOLA ESGRIGNOLI; SPINOLA-CASTRO, ANGELA M.; DIAS DA SILVA, MAGNUS R. Cosegregation of a novel mutation in the sixth transmembrane segment of the luteinizing/choriogonadotropin hormone receptor with two Brazilian siblings with severe testotoxicosis. ENDOCRINE RESEARCH, v. 42, n. 2, p. 117-124, 2017. Web of Science Citations: 3.
NASCIMENTO, FABRICIO P.; CARDOSO, MIRIAN G.; LINDSEY, SUSAN C.; KUNII, ILDA S.; VALENTE, FLAVIA O. F.; KIZYS, MARINA M. L.; DELCELO, ROSANA; CAMACHO, CLEBER P.; MACIEL, RUI M. B.; DIAS-DA-SILVA, MAGNUS R. Analysis of somatic mutations in BRAF, CDKN2A/p16 and PI3KCA in patients with medullary thyroid carcinoma. MOLECULAR MEDICINE REPORTS, v. 13, n. 2, p. 1653-1660, FEB 2016. Web of Science Citations: 2.
KIZYS, MARINA M. L.; NESI-FRANCA, SUZANA; CARDOSO, MIRIAN G.; HARADA, MICHELLE Y.; MELO, MARIA CLARA C.; CHIAMOLERA, MARIA IZABEL; DIAS-DA-SILVA, MAGNUS R.; MACIEL, RUI M. B. The absence of mutations in homeobox candidate genes HOXA3, HOXB3, HOXD3 and PITX2 in familial and sporadic thyroid hemiagenesis. JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM, v. 27, n. 3-4, p. 317-322, MAR 2014. Web of Science Citations: 3.

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