Two compound heterozygous mutations (c.215delA/c.2422T-->C and c.387delC/c.1159G-->A) in the thyroid peroxidase gene responsible for congenital goitre and iodide organification defect.

BACKGROUND: Iodide organification defects are frequently but not always associated with mutations in the thyroid peroxidase (TPO) gene and characterized by a positive perchlorate discharge test. These mutations phenotypically produce a congenital goitrous hypothyroidism, with an autosomal recessive mode of inheritance.

OBJECTIVES: In the present study we extended our initial molecular studies in six unrelated patients heterozygous for the TPO mutations, in order to identify the second mutation in this autosomal recessive disease.

METHODS: The promoter and the complete coding regions of the human TPO and DUOXA2 genes, along with the flanking regions of each intron were analysed by direct DNA sequencing.

RESULTS: Four different inactivating TPO mutations were identified in two patients: two novel mutations (c.215delA [p.Q72fsX86] and c.1159G-->A [p.G387R]) and two previously reported (c.387delC [p.N129fsX208] and c.2422T-->C [p.C808R]), confirming the inheritance of two different compound heterozygous mutations, c.215delA/c.2422T-->C and c.387delC/c.1159G-->A. The remaining four patients did not show additional inactivating mutations in the TPO gene and all had only the wild type sequencing in the DUOXA2 gene.

CONCLUSIONS: We have reported two patients with iodide organification defect caused by two compound heterozygous mutations, c.215delA/c.2422T-->C [p.Q72fsX86/p.C808R] and c.387delC/c.1159G-->A [p.N129fsX208/p.G387R], in the TPO gene and four patients with monoallelic TPO defect. Identification of the molecular basis of this disorder might be helpful for understanding the pathophysiology of congenital hypothyroidism.