Abstract

Congenital hypothyroidism (CH) occurs with a relatively alarming prevalence in infants, and if not diagnosed and treated in time, it can have devastating consequences for the development of the nervous system. CH is associated with genetic changes in several genes that encode transcription factors responsible for thyroid development, including mutations in the NK2 homeobox 1 (NKX2.1) gene, which encodes the thyroid transcription factor-1 (TTF-1). Although CH is frequently observed in pediatric populations, there is still a limited understanding of the genetic factors and molecular mechanisms contributing to this disease. The sequence of the NKX2.1 gene was investigated in 75 pediatric patients with CH by polymerase chain reaction (PCR), single-stranded conformation polymorphism (SSCP), and direct DNA sequencing. Four missense heterozygous variations were identified in exon 3 of the NKX2.1 gene, including three novel missense variations, namely c.708A>G, p.Gln202Arg; c.713T>G, p.Tyr204Asp; c.833T>G, p.Tyr244Asp, and a previously reported variant rs781133468 (c.772C>G, p.His223Gln). Importantly, these variations occur in highly conserved residues of the TTF-1 DNA-binding domain and were predicted by bioinformatics analysis to alter the protein structure, with a probable alteration in the protein function. These results indicate that nucleotide changes in the NKX2.1 gene may contribute to CH pathogenesis.