New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter

PETEIRO-GONZALEZ, D. ; LEE, J.; RODRIGUEZ-FONTAN, J. ; CASTRO-PIEDRAS, I.; CAMESELLE-TEIJEIRO, J. ; BEIRAS, A. ; BRAVO, S. B. ; ALVAREZ, C. V. ; HARDY, D. M. ; TARGOVNIK , HÉCTOR MANUEL; ARVAN, PETER; LADO-ABEAL, JOAQUÍN

JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM

ENDOCRINE SOC

Lugar: Chevy Chase; Año: 2010 vol. 95 p. 3522 - 3526

0021-972X

Context: Thyroglobulin (TG) gene mutations cause congenital hypothyroidism (CH) with goiter. A founder effect has been proposed for some frequent mutations. Mutated proteins have a defect in intracellular transport causing intracellular retention with ultrastructural changes that resemble an endoplasmic reticulum storage disease. Objective: To reveal new aspects of thyroglobulin pathophysiology through clinical, cellular, molecular, and genetic studies in a family presenting with CH due to TG mutations from Galicia, an iodine-deficient area of Spain. Design: The included clinical evaluation of family members,DNAsequencing for TG gene mutation and haplotyping analysis, ultrastructural analysis of thyroid tissue specimens from affected subjects, analysis of effects of mutations found on TG gene transcription, and in vitro studies of cellular production and secretion of mutated proteins. Setting: Locations included primary care and university hospitals. Results: Family members with CH, mental retardation, and goiter were compound heterozygous for c.886C3T (p.R277X) and g.IVS35_1delG. For c.886C3T, a founder effect cannot be excluded, and its transcription was hardly detectable. g.IVS35_1delG caused an in-frame deletion in exon 35 and produced a protein that, although synthesized, could not be secreted. Ultrastructural analyses showed morphological changes consistent with an endoplasmic reticulum storage disease. Conclusion: The shorter thyroglobulin resulting from the novel g.IVS35_1delGwasretained within the endoplasmic reticulum of thyrocytes,andtogether with p.R227X caused severe hypothyroidism with goiter. p.R277X, the most commonly described TG mutation, is caused by a TG exon-7 highly mutation-prone region, and the possibility thatsomecases were introduced to South America from Galicia cannot be excluded.