A premature stopcodon in thyroglobulin messenger RNA results in familial goiter and moderate hypothyroidism

Impaired thyroglobulin (Tg) synthesis is one of the putative causes for dys hormonogenesis of the thyroid gland. This type of hypothyroidism is charact erized by intact iodide trapping, normal organification of iodide, and usua lly low serum Tg levels in relation to high TSH, and when untreated the pat ients develop goiter. In thyroid tissue from a 13-yr-old patient suspected of a thyroglobulin synthesis defect, the Tg mRNA was studied. The complete coding region of 8307 bp was directly sequenced and revealed a homozygous p oint mutation: a C886T transition in exon 7. Upon translation this mutation would result in a stopcodon at amino acid position 277, replacing the argi nine residue. A Tg cDNA construct containing the mutation was expressed in rabbit reticulocyte lysate resulting in a truncated protein of 30 kDa. Expr ession in the presence of microsomal membranes resulted in a gel shift of t his Tg molecule, indicating glycosylation ability. Two other siblings had a clinical presentation like the index patient, while their parents were una ffected. Additional restriction fragment length polymorphism analysis of th e pedigree verified that the homozygous nonsense mutation cosegregated with the clinical phenotype. Clinically, hypothyroidism was not severe in the a ffected siblings because the truncated Tg glycoprotein was still capable of thyroid hormonogenesis.