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

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Abstract
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 [1, 2]. 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 β‐carbon of the amino acid residue at position 354. Hence, this hydroxyl group is essential for NIS function.