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

Academic Medical Center (S.A.R.v.d.G., C.R.-S., G.J.M.V., J.J.M.d.V.), University of Amsterdam, Emma Children’s Hospital AMC, Laboratory of Pediatric Endocrinology, Amsterdam, The Netherlands; Laboratório de Tireóide (LIM-25) (C.S., G.M.-N.), Hospital das Clínicas, Universidade de Sâo Paulo, Sâo Paulo 01065–970, Brazil; Division Genética (H.M.T.), Hospital de Clínicas "José de San Martin", Facultad de Medicina and Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, 1120, Buenos Aires, Argentina

Address all correspondence and requests for reprints: Simone A.R. van de Graaf, Academic Medical Center G2–123, Laboratory of Pediatric Endocrinology, PO Box 22700, 1100 DE, Amsterdam, The Netherlands, Fax: **31.20.6916396, e-mail: S.A.vandeGraaf@amc.uva.nl.

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.

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