HYPOTHYROIDISM IN A BRAZILIAN KINDRED DUE TO IODIDE TRAPPING DEFECT CAUSED BY A HOMOZYGOUS MUTATION IN THE SODIUM IODIDE SYMPORTER GENE/

A 36 year old man with a large goiter was suspected of having iodide ( I-) transport defect based on low thyroidal and salivary gland radioio dide uptake. Thyroid surgery was performed, because thyroid cytology c ould not exclude a malignancy. Sequencing of the entire Na+/I- symport er (NIS) cDNA derived from thyroidal mRNA revealed a homozygous substi tution of the normal cytosine in nucleotide (nt) 1163 with an adenine, resulting in a stop (TGA) at codon 272. This nonsense mutation produc es a truncated NIS with undetectable I- transport activity when expres sed into COS-7 cells. Genotyping confirmed that the propositus was hom ozygous for the mutation whereas his unaffected mother, son, and pater nal aunt were heterozygous. This nt substitution was not detected in a ny of 50 normal individuals, ruling out a polymorphism. While the homo zygous mutant NIS-272X causes congenital hypothyroidism, expression of one normal allele in the heterogygote (C272X) is sufficient to mainta in active thyroidal I- uptake and function. (C) 1997 Academic Press.