Mutation analysis of the NKX2.5 gene in Iranian pediatric patients with congenital hypothyroidism

Background: The embryonic development of the thyroid gland is regulated by the expression of several candidate genes which are related to congenital hypothyroidism. These genes include the numerous critical thyroid transcription factors such as NKX2.1, NKX2.5, FOXE1, and PAX8. The molecular analysis of these loci will be essential to the explanation of the participation of these transcription activators in the etiology of hypothyroidism. Among them, the role of NKX2.5 is important during the early thyroid morphogenesis and in controlling thyroidal cell differentiation and migration. Importantly, NKX2.5 change nucleotides are recognized to be central to the genesis of congenital hypothyroidism. Methods: A case-control study was conducted in 65 unrelated patients, diagnosed with primary congenital hypothyroidism and all of them were diagnosed according to the clinical presentations of thyroid hypoplasia and without cardiovascular defects. Mutational screening of the entire NKX2-5 coding sequence was performed in a cohort of pediatric patients by PCR-SSCP and direct sequencing. Results: We identified two known variations 73C>T (R25C) and 63A>G (E21E) in patients with thyroid hypothyroidism. Both of them are located in conserved region of the gene and previously reported in cases with thyroid dysgenesis and congenital heart defects. There was a significance association between 63A>G variation with primary hypothyroidism (p = 0.003). Conclusions: These SNPs are probably related to thyroid hypoplasia because the allele frequency of the 63A>G polymorphism was significantly different in patients and controls and also R25C variation not observed in healthy cases.