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Molecular analysis of patients with congenital hypothyroidism by iodine defect

Grant number: 12/00324-8
Support Opportunities:Regular Research Grants
Duration: October 01, 2012 - September 30, 2014
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Suemi Marui
Grantee:Suemi Marui
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil


The main role of the thyroid gland is the production of T3 and T4 that are essential for development and regulation of several functions in the body. Congenital hypothyroidism (CH) is a systemic metabolic disorder, with insufficient production of thyroid hormones in the neonatal period. HC can be caused by embryonic development defects of thyroid gland (dysgenesis) or in the hormones synthesis defect (dyshormonogenesis). Several genes are involved in thyroid dyshormonogenesis, including TPO gene (a protein that is responsible for iodine oxidation, thyroglobulin iodination and tyrosine coupling during the thyroid hormones formation), and DUOX2 gene (enzyme responsible for H2O2 generation during iodine organification). In our previous study (FAPESP 2008/04786-0), we performed the molecular study of patients with clinically and laboratory suspect of iodide organification defect, we evaluated TPO gene in seven patients. We identified the mutation p.Q660E and a novel mutation p.R584Q, and in four patients we did not identify mutations. To determine TPO activity of p.R584Q mutant, HEK293 cells will be transfected with pCMV plasmids that contains the TPO wild type and TPO mutated genes. We will evaluate protein enzymatic activity by iodide oxidation method. The results will determine the effect of p.R584Q mutation in TPO enzymatic activity, which can correlate the clinical and laboratory findings of patients with dyshomonogenesis due to TPO defect. We will also perform molecular analysis of DUOX2 gene in these 4 patients, searching for mutations that would justify dyshormonogenesis. We will amplify the fragments of DUOX2 gene by PCR, the amplified products will be automatically sequenced and compared with sequences obtained from the Internet database (GeneBank). The results will establish the correlation among clinical and laboratory findings of patients, defining the cause of HC. (AU)

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