Identification of a structural requirement for thyroid Na+/I- symporter (NIS) function from analysis of a mutation that causes human congenital hypothyroidism.

Patients with congenital lack of I transport do not accumulate I in their thyroids, often resulting in severe hypothyroidism. A single amino acid substitution in the thyroid Na+/I- symporter (NIS), proline replacing threonine at position 354 (T354P), was recently identified as the cause of this condition in two independent patients. Here we report that the lack of I- transport activity in T354P NIS generated by site-directed mutagenesis, is not due to a structural change induced by proline, but rather to the absence of a hydroxyl group at the beta-carbon of the amino acid residue at position 354. Hence, this hydroxyl group is essential for NIS function.