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Purpose of Review: To perform an update review on thyroglobulin gene mutations associated with congenital hypothyroidism, thyroid cancer, and autoimmunity., Recent Findings: Forty-two thyroglobulin mutations have been identified in dyshormonogenetic congenital hypothyroidism. Clinical and laboratory criteria defining defective thyroglobulin synthesis are mostly related to thyroglobulin mutations, generally caused by intracellular thyroglobulin transport defects to the colloid rather than defects in thyroid hormones synthesis. Some mutated thyroglobulin may escape the rigorous chaperone control and reach the colloid, allowing a wide phenotypic spectrum that includes euthyroidism in an adequate iodine environment. In some patients, continuous levothyroxine treatment does not reduce elevated serum thyroid-stimulating hormone (TSH) levels that may lead to goiter development. Prenatally, inactive mutant thyroglobulin will not be able to synthesize thyroid hormones and may increase pituitary thyrotroph threshold for thyroid hormone feedback. Congenital goiter is a risk factor for thyroid cancer and some thyroglobulin variants may confer susceptibility to thyroid autoimmunity., Summary: Advances in the understanding of thyroglobulin genetic defects and its severity should allow researchers to perform adequate molecular diagnosis, genetic counseling, and intrauterine treatment to prevent subtle deficits in central nervous system development. This knowledge should improve the understanding of physiological functions of the thyroid and influence of nutritional iodine.

Context: Thyroglobulin (TG) is a large glycoprotein and functions as a matrix for thyroid hormone synthesis. TG gene mutations give rise to goitrous congenital hypothyroidism (CH) with considerable phenotype variation., Objectives: The aim of the study was to report the genetic screening of 15 patients with CH due to TG gene mutations and to perform functional analysis of the p.A2215D mutation., Design: Clinical evaluation and DNA sequencing of the TG gene were performed in all patients. TG expression was analyzed in the goitrous tissue of one patient. Human cells were transfected with expression vectors containing mutated and wild-type human TG cDNA., Results: All patients had an absent rise of serum TG after stimulation with recombinant human TSH. Sequence analysis revealed three previously described mutations (p.A2215D, p.R277X, and g.IVS30+1G>T), and two novel mutations (p.Q2142X and g.IVS46-1G>A). Two known (g.IVS30+1G/p.A2215D and p.A2215D/p.R277X) and one novel (p.R277X/g.IVS46-1G>A) compound heterozygous constellations were also identified. Functional analysis indicated deficiency in TG synthesis, reduction of TG secretion, and retention of the mutant TG within the cell, leading to an endoplasmic reticulum storage disease, whereas small amounts of mutant TG were still secreted within the cell system., Conclusion: All studied patients were either homozygous or heterozygous for TG gene mutations. Two novel mutations have been detected, and we show that TG mutation p.A2215D promotes the retention of TG within the endoplasmic reticulum and reduces TG synthesis and secretion, causing mild hypothyroidism. In the presence of sufficient iodine supply, some patients with TG mutations are able to compensate the impaired hormonogenesis and generate thyroid hormone.

Objective: To extend the molecular analysis of the IVS30+1G>T intronic thyroglobulin (TG) mutation, and to report the eleven year follow-up of the affected patients. METHOSD: Two siblings with severe congenital hypothyroidism with fetal and neonatal goiter, harboring the IVS30+1G>T mutation were included. Nodular and non-nodular thyroid tissue specimens were collected. Specific thyroid genes expression was evaluated by real-timePCR and by immunohistochemistry., Results: In non-nodular tissue specific thyroid genes mRNA were reduced when compared to normal thyroid sample. In the nodule, TPO and NIS expression was very low. Microscopic examinations showed very large follicular-lumina and swollen vesicles of endoplasmatic-reticulum. Strong cytoplasmatic and low follicular-lumen TG immunostaining were detected. Intracellular NIS, membrane TPO and TSHR immunostaining had higher positivity in non-nodular sample. Both patients had a long-term adequate developmental outcome, besides one patient have been lately-treated., Conclusions: IVS30+1G>T mutation not only lead to very enlarge endoplasmatic-reticulum, but also to alterations of specific thyroid genes expression. The clinical evolution of patients harboring these mutations strengthen the concept of the influence of environment, like iodine nutrition, to determine the final phenotypic appearance.

Background: Thyroglobulin (Tg) is a large glycoprotein that is intimately involved in the biosynthesis of thyroxine and triiodothyronine. At least 38 mutations have been described in the Tg gene that are associated with varying degrees of hypothyroidism. We studied the Tg gene in four related subjects with congenital hypothyroidism., Summary: We found a novel compound heterozygous constellation (IVS30 + 1G>T/A2215D) in a brother and sister and one previously described related mutation (IVS30+1G>T) in their two sibling second degree cousins. The brother with the IVS30 + 1G>T/A2215D mutation and the two siblings with the IVS30+1G>T mutation had fetal or neonatal goiter and all had hypothyroidism., Conclusions: This study further confirms the association of the IVS30+G>T mutation of the Tg gene with hypothyroidism. Computer analysis predicts that the A2215D mutation, first reported here, should cause structural instability of Tg but when present as a compound heterozygous mutation with IVS30+G>T/A its effect is unclear but is likely to be influenced by iodine intake.

Mutations of the thyroperoxidase (TPO) gene have been reported as being the most severe and frequent abnormality in thyroid iodide organification defect (IOD) causing goitrous congenital hypothyroidism. The objective of this study was to screen and subsequently identify TPO gene mutations in patients with congenital hypothyroidism with evidence of total iodine organification defects (TIOD) or partial iodine organification defect (PIOD) as defined by the perchlorate discharge test. Seven goitrous patients with TIOD and seven patients with PIOD, from three and five unrelated families, respectively, were studied. We were able to detect different TPO genes mutations in patients with TIOD and PIOD. In TIOD families the results were as follows: (1) a homozygous GGCC insertion at exon 8, position 1277 (family 1); (2) compound heterozygosity with a GGCC insertion at exon 8 (1277) and a nucleotide substitution in exon 11 (2068G>C) (family 2); (3) compound heterozygosity with the mutation 2068G>C in exon 11 and a C insertion in exon 14 between positions 2505-2511 (family 3). In patients with PIOD we have detected: (1) only one heterozygous mutation in two families (4 and 5), in exons 11 and 10 (2084G>A and 1780C>A); (2) a compound heterozygous condition in one family (family 6), with mutations, respectively in exons 8 and 10 (1242G>T and 1780C>A); (3) only polymorphisms (family VII) and (4) a heterozygous mutation in the first base of the border exon/intron 9 +1G>T (family VIII). We did not detect inactivating mutations in exons 11, 16, and 21 of the THOX2 gene where mutations have been previously described. We concluded that homozygous and compound heterozygous mutations found in TIOD characterized the autosomal recessive mode of inheritance and will translate a nonfunctional protein or a protein that may not reach the apical membrane. As for PIOD, the majority of the studied kindreds had only heterozygous mutations and/or polymorphisms. It is conceivable that these TPO gene sequence alterations may partially affect the functional state of the translated protein or affect its transport to the apical membrane.