Novel mutations of the thyroid peroxidase gene in patients with permanent congenital hypothyroidism.

OBJECTIVE

It is suggested that iodide organification defects account for 10% of all cases with congenital hypothyroidism (CH). One candidate gene for these defects is the thyroid peroxidase (TPO) gene.

DESIGN

Exons 2, 8-10 and 14 of the TPO gene were examined in 30 patients with permanent CH without a family history of CH. This group was characterized by the presence of an orthotopic thyroid gland and elevated TSH levels.

METHODS

The mutational screening was performed by single-strand conformational polymorphism followed by sequence analysis of fragments with abnormal migration patterns and by restriction enzyme analysis.

RESULTS

In four patients we were able to identify mutations on both alleles which have not been described so far. One patient was a carrier of a new homozygous point mutation in exon 9 resulting in an exchange from Leu to Pro at codon 458. Another patient was found to be compound heterozygous for two mutations, a 20 bp duplication in exon 2 and a new mutation in exon 9 (Arg491His). Two brothers of consanguineous parents showed a homozygous T deletion in exon 14 at position 2512.

CONCLUSIONS

Our findings confirm the genetic heterogeneity of TPO defects and support the suggested prevalence of organification defects.