A novel mutation in the sodium/iodide symporter gene in the largest family with iodide transport defect.

We previously reported nine children with an autosomally recessive form of congenital hypothyroidism due to an iodide transport defect in a large Hutterite family with extensive consanguinity living in central Canada. Since the original report, we have diagnosed congenital hypothyroidism by newborn TSH screening in 9 additional children from the family. We performed direct sequencing of the PCR products of each NIS (sodium/iodide symporter) gene exon with flanking introns amplified from genomic DNA extracted from peripheral blood cells of the patients. We identified a novel NIS gene mutation, G395R (Gly395-->Arg; GGA-->AGA), in 10 patients examined in the present study. All of the parents tested were heterozygous for the mutation, suggesting that the patients were homozygous. The mutation was located in the 10th transmembrane helix. Expression experiments by transfection of the mutant NIS complimentary DNA into COS-7 cells showed no perchlorate-sensitive iodide uptake, confirming that the mutation is the direct cause of the iodide transport defect in these patients. A patient who showed an intermediate saliva/serum technetium ratio (14.0; normal, > or = 20) and was considered to have a partial or less severe defect in the previous report (IX-24) did not have a NIS gene mutation. It is now possible to use gene diagnostics of this unique NIS mutation to identify patients with congenital hypothyroidism due to an iodide transport defect in this family and to determine the carrier state of potential parents for genetic counseling and arranging rapid and early diagnosis of their infants.