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. ; ALVAREZ, C.V.; HARDY, D.M.; TARGOVNIK , HÉCTOR MANUEL; ARVAN, PETER; LADO-ABEAL, JOAQUÍN

París

Congreso; 14th International Thyroid Congress; 2010

European Thyroid Association, American Thyroid Association, Asia & Oceania Thyroid Association, Latin American Association

Abstract: 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: Clinical evaluation of family members. DNA sequencing for TG gene mutation.  Haplotyping of nineteen TG markers and comparison with those from five Argentinian and one Brazilian families bearing c.886C>T[p.R277X]. Ultrastructural analysis of thyroid tissue specimens from affected subjects. Analysis of effects of mutations found on TG gene transcription. In vitro studies of cellular production and secretion of mutated proteins. 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 (Figure 1). Ultrastructural analyses showed a marked dilatation of RER, a morphological change consistent with an endoplasmic reticulum storage disease (Figure 1). Conclusion: The shorter thyroglobulin resulting from the novel g.IVS35+1delG was retained within the endoplasmic reticulum of thyrocytes, and together 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 haplotype analysis cannot rule out the hypothesis that some cases were introduced to South America by members of this Galician family. Grants support: This study was supported by the Spanish Ministerio de Educación (SAF2006-02542 to J L-A and BFU2007-60571 to CVA), by Xunta de Galicia (PGIDIT04PXIC20801PN to J L-A, PGIDIT06PXIB 208360PR to J L-A, and PGIDIT06PXIB208107PR to CVA), by the Spanish Instituto de Salud Carlos III (PI060209 and PS09/02050to J C-T) and NIH (DK40344 to PA).