SCREENING FOR MUTATIONS OF THE HUMAN THYROID PEROXIDASE GENE IN PATIENTS WITH CONGENITAL HYPOTHYROIDISM

While congenital hypothyroidism in 80-90% of the affected individuals is caused by thyroid dysgenesis (athyrosis, ectopy or hypoplasia), hyp othyroidism in patients with a thyroid gland of normal position and si ze can be due to regulatory or enzymatic defects of thyroid hormone bi osynthesis. Beside defects of thyroglobulinsynthesis, defects of the s odium-iodide-transporter or the TSH-receptor, a defect of the thyroidp eroxidase, the key-enzyme of thyroid hormone biosynthesis, can cause a total iodide organification defect and thereby congenital hypothyroid ism. We screened 14 of 103 patients (13.6%) with non familial congenit al hypothyroidism and a normally developed thyroid gland detected by t he newborn screening program with the PCR-SSCP (single-stranded-confor mational-polymorphism) technique for mutations in the exons 2, 8, 9, 1 0 and 14 of the human thyroperoxidase gene, and in which mutations had been described previously in Dutch and Brazilian families with total organification defects. Most of the previously reported mutations were found in exons 8, 9 and 10 which code for the caralytic part of the e nzyme. In two patients a GGCC-duplication in exon 8 was detected leadi ng to a premature stop codon in exon 9. While one patient without neon atal goiter was homozygous for this mutation, the second patient was o nly heterozygous thus demanding another mutation on the second TPO-all el to explain the phenotype. Since the GGCC duplication is easily demo nstrable by a NaeI digestion, because it creates a restriction site fo r this enzyme, screening for this mutation is indicated since it is ea sy to perform. In contrast to the perchlorate discharge test molecular genetic studies are less invasive, but as useful in making 8 definiti ve diagnosis in the individual patient. Furthermore it is the first fe asible step to study the etiology and epidemiology of the so far only putative defects of thyroid hormone biosynthesis leading to congenital hypothyroidism.