A novel mutation in the TPO gene in goitrous hypothyroid patients with iodide organification defect

OBJECTIVE To screen and subsequently sequence the TPO gene for mutations in patients with congenital goitre, hypothyroidism and evidence for an organi fication defect (positive perchlorate discharge test). PATIENTS We have studied seven hypothyroid and congenitally goitrous patien ts from three unrelated families. DESIGN AND MEASUREMENTS We have measured serum thyroid hormone levels, I-13 1 uptake, serum TSH and serum Tg concentrations. Denaturing gradient gel el ectrophoresis (DGGE) of PCR amplified genomic DNA was used to screen for mu tations in the TPO gene. RESULTS DGGE identified the presence of two frameshift mutations: a GGCC du plication in exon 8 (homozygous in one family and heterozygous in the other family) and a heterozygous insertion of a single nucleotide (C) at positio n 2505-2511 in exon 14. In addition, we have detected an alteration in exon 11, not yet described in the literature, derived from a single nucleotide substitution of a C to G at position 2008, altering the well-conserved amin o acid domain among the peroxidases superfamily. This mutation in exon II w as present in two families that showed heterozygous mutation for exon 8 or for exon 14. CONCLUSIONS These results could support the hypothesis for a putative compo und heterozygosity pattern in the affected patients. The altered phenotype (goitre and hypothyroidism since birth) seems justifiable in view of the po ssible inactivating character of this novel mutation in exon 11.