New insights into thyroglobulin pathophysiology revealed by the study of a family with congenital goiter.
BACKGROUND
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.


METHODS
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.


METHODS
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.


CONCLUSIONS
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 possibility that some cases were introduced to South America from Galicia cannot be excluded.
Peteiro-Gonzalez
D
D
Unidade de Enfermedades Tiroideas e Metabolicas, School of Medicine, University of Santiago de Compostela, E-15782 Spain
Lee
J
J
Rodriguez-Fontan
J
J
Castro-Piedras
I
I
Cameselle-Teijeiro
J
J
Beiras
A
A
Bravo
S B
SB
Alvarez
C V
CV
Hardy
D M
DM
Targovnik
H M
HM
Arvan
P
P
Lado-Abeal
J
J
D000328:Adult; D015153:Blotting, Western; D002478:Cells, Cultured; D003409:Congenital Hypothyroidism / Q000235:genetics*; D005820:Genetic Testing; D006042:Goiter / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D013030:Spain; D013954:Thyroglobulin / Q000235:genetics*
D013954:Thyroglobulin
J Clin Endocrinol Metab. 2005 Jun;90(6):3766-70
15769978
J Endocrinol. 2007 Oct;195(1):167-77
17911408
Am J Hum Genet. 1998 Aug;63(2):474-88
9683596
J Clin Endocrinol Metab. 2004 Feb;89(2):646-57
14764776
Nature. 1985 Aug 15-21;316(6029):647-51
3855243
Oncogene. 2003 Oct 30;22(49):7819-30
14586408
J Clin Invest. 2008 Aug;118(8):2950-8
18596923
J Cell Biol. 1996 May;133(3):517-27
8636228
J Clin Invest. 1996 Dec 15;98(12):2838-44
8981932
Clin Endocrinol (Oxf). 1975 Jul;4(4):363-92
1157342
J Biol Chem. 2009 May 8;284(19):12752-61
19276074
Mol Endocrinol. 2008 Feb;22(2):477-84
17916655
J Clin Endocrinol Metab. 1999 Jul;84(7):2537-42
10404833
Eur J Endocrinol. 2001 Oct;145(4):485-96
11581009
Clin Endocrinol (Oxf). 2007 Sep;67(3):351-7
17532758
Thyroid. 2005 Sep;15(9):1021-33
16187910
Biochim Biophys Acta. 1975 Sep 9;405(1):11-22
1174561
J Clin Endocrinol Metab. 2009 Aug;94(8):2938-44
19509106
Clin Chim Acta. 2006 Dec;374(1-2):8-24
16870170