A Premature Stopcodon in Thyroglobulin Messenger RNA Results in Familial Goiter and Moderate Hypothyroidism

Abstract

Impaired thyroglobulin (Tg) synthesis is one of the putative causes for dyshormonogenesis of the thyroid gland. This type of hypothyroidism is characterized by intact iodide trapping, normal organification of iodide, and usually low serum Tg levels in relation to high TSH, and when untreated the patients 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 point mutation: a C886T transition in exon 7. Upon translation this mutation would result in a stopcodon at amino acid position 277, replacing the arginine residue. A Tg cDNA construct containing the mutation was expressed in rabbit reticulocyte lysate resulting in a truncated protein of 30 kDa. Expression in the presence of microsomal membranes resulted in a gel shift of this Tg molecule, indicating glycosylation ability. Two other siblings had a clinical presentation like the index patient, while their parents were unaffected. Additional restriction fragment length polymorphism analysis of the pedigree verified that the homozygous nonsense mutation cosegregated with the clinical phenotype. Clinically, hypothyroidism was not severe in the affected siblings because the truncated Tg glycoprotein was still capable of thyroid hormonogenesis.

Primary congenital hypothyroidism: defects in iodine pathways

“…A homozygous C886T transition in exon 7 results in the replacement of an Arg residue into a premature stop codon at amino acid position 277 in TG upon translation (43). Clinically, hypothyroidism, observed in three related patients, was not severe indicating that the short TG fragment was still able to produce thyroid hormone, a phenomenon that was also observed in the goat model and in in vitro experiments (44).…”

The cholinesterase-like domain of thyroglobulin functions as an intramolecular chaperone

“…One might predict that a highly truncated Tg with fewer disulfide bonds and preservation of crucial amino acids for thyroid hormone formation (10,11) would allow survival without the need of intramolecular chaperone or escort functions. Indeed, there is speculation that such a short aminoterminal portion of Tg may be all that is required for human survival, which requires ongoing thyroid hormone synthesis (36). However, evolutionary and environmental circumstances (i.e., iodide unavailability on the earth's crust) have promoted development of a more complex Tg structure for iodide storage in vertebrate organisms (1).…”

Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

“…Three offspring of a consanguineous marriage presenting with mild hypothyroidism associated with defective TG synthesis were found to have a premature stop codon in exon 7 (886C>T; R296X; originally described as p.R277X) (82). This truncated TG still contains the main hormonogenic sites in the mature polypeptide (acceptor tyrosine 5 and donor tyrosine 149) and appears to retain partial hormone synthesis.…”