Congenital hypothyroidism caused by a unique thyroid peroxidase allele containing two mutations, C1708T and C2737T

Thyroid peroxidase (TPO) is a key enzyme of thyroid hormone biosynthesis. TPO abnormality is considered to be a major cause of congenital hypothyroidism (CH) with total iodide organification defect. In the present study, we examined the TPO gene of three siblings, 3 and 2 year-old brothers and a newborn sister, with severe CH. All 17 exons and the promoter region in the TPO gene were directly sequenced using genomic DNA. Two homozygous mutations, C1708T and C2737T, were found in all three patients. The C1708T mutation introduces a premature terminal codon, which is suggested to be a cause of CH. The other mutation, C2737T, and 13 single nucleotide polymorphisms in the patients' TPO genes were also detected as homozygous. We suspect that the mutated alleles were inherited from a single, common ancestor. The haplotype including the two mutations was conserved in a narrow region between D2S2268 and D2S323 microsatellite markers on the end of chromosome 2.