Artículo
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, Hector Manuel
; Arvan, P.; Lado Abeal, Joaquin
Fecha de publicación:
07/2010
Editorial:
Endocrine Society
Revista:
Journal of Clinical Endocrinology and Metabolism
ISSN:
0021-972X
e-ISSN:
1945-7197
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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, DNA sequencing 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.886C→T (p.R277X) and g.IVS35+1delG. For c.886C→T, 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+1delG was retained 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.
Palabras clave:
Congenital Goiter
,
Hypothyroidism
,
Thyroglobulin
,
Mutation
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Identificadores
Colecciones
Articulos(INIGEM)
Articulos de INSTITUTO DE INMUNOLOGIA, GENETICA Y METABOLISMO
Articulos de INSTITUTO DE INMUNOLOGIA, GENETICA Y METABOLISMO
Citación
Peteiro Gonzalez, D.; Lee, J.; Rodriguez Fontan, J.; Castro Piedras, I.; Cameselle Teijeiro, J.; et al.; New Insights into Thyroglobulin Pathophysiology Revealed by the Study of a Family with Congenital Goiter; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 95; 7; 7-2010; 3522-3526
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