Genes Associated With Multinodular Goiter

In contrast to sporadicgoiters, caused by spontaneous recessive genomic variation, most cases of familial goiter present an autosomal dominant pattern of inheritance, indicating predominant genetic defects. Gene-gene interactions or various polygenic mechanisms (i.e. synergistic effects of several variants or polymorphisms) could increase the complexity of the pathogenesis of nontoxic goiter and offer an explanation for its genetic heterogeneity. A strong genetic predisposition is indicated by family and twin studies. Thus, children of parents with goiter have a significantly higher risk of developing goiter compared with children of nongoitrous parents. The high incidence in females and the higher concordance  in monozygotic than in dizygotic twins also suggested a genetic predisposition. Moreover, there is preliminary evidence of a positive family history for thyroid diseases in those who have postoperative relapse of goiter, which can occur from months to years after surgery.

Defects in genes that play an important role in thyroid physiology and thyroid hormone synthesis could predispose to the development of goiter, especially in case of borderline or overt iodine deficiency. Such defects could lead to dyshormonogenesis as an immediate response, thereby indirectly explaining the nodular transformation of the thyroid as late consequences of dyshormonogenesis, as a form of maladaptation.

The genes that encode the proteins involved in thyroid hormone synthesis, such as the thyroglobulin-gene (TG-gene), the thyroid peroxidase-gene (TPO-gene),
the sodium – iodide – symporter-gene (SLC5A5), the Pendred syndrome-gene (SLC26A4), the TSH receptor-gene (TSH-R-gene), the iodotyrosine deiodinase (DEHAL 1) and the thyroid oxidase 2 gene 3 (DUOX2) are convincing candidate genes in familial  euthyroid goiter. Originally, several mutations in these genes were identified in patients with congenital hypothyroidism. However, in cases of less severe functional impairment, with can still be compensated (kompensasi), a contribution of variants of these genes in the etiology of nontoxic goiter is possible.

1.     Tg = thyroglobulin gene

a.       The official name of the TG gene

The official name of this gene is “thyroglobulin.” TG is the gene's official symbol. The TG gene is also known by other names.

b.      The normal function of the TG gene

The TG gene provides instructions for making a protein called thyroglobulin, one of the largest proteins in the body. This protein is found only in the thyroid gland, a butterfly-shaped tissue in the lower neck. Thyroglobulin combines with iodine and is modified and broken down to release small molecules known as thyroid hormones. Thyroid hormones play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). Thyroglobulin also serves as a protein storehouse for iodine and inactive thyroid hormone until these substances are neded.

c.       The TG gene related to health conditions

Congenital hypothyroidism - caused by mutations in the TG gene

Several TG gene mutations have been identified in people with a mild to severe thyroid hormone deficiency. When the deficiency is severe enough during fetal development, it can cause congenital hypothyroidism. The mutations either delete a small segment of the TG gene or change one of the DNA building blocks (base pairs). As a result, the 3-dimensional shape of thyroglobulin is altered, reducing the amount of properly structured protein that is available for thyroid hormone production. In most affected individuals, the thyroid gland is enlarged (goiter) in an attempt to compensate for reduced hormone production.

Autoimmune disorders - associated with the TG gene

A major cause of thyroid disease is autoimmunity, in which the body's immune response turns against itself. The autoimmune response is triggered by a combination of genetic and environmental factors and involves the production of large Y-shaped proteins called antibodies or immunoglobulins. Instead of attacking foreign substances such as toxins or proteins from bacteria and viruses, antibodies sometimes inappropriately attack thyroid proteins. Antibodies that attack the body's own proteins are called autoantibodies. The presence of autoantibodies to thyroglobulin is an indication of autoimmune thyroid disease.

       Hashimoto thyroiditis is a common type of autoimmune thyroid disease. Individuals with Hashimoto thyroiditis may have reduced thyroid activity (hypothyroidism) and an enlarged thyroid gland (goiter). Some people with this disorder have autoantibodies to thyroglobulin.

Other disorders - caused by mutations in the TG gene

TG gene mutations have also been identified in some people who have a goiter but normal or near normal thyroglobulin levels. These mutations either delete part of the TG gene or change one of the DNA building blocks (base pairs). As a result, the 3-dimensional shape of thyroglobulin is altered, reducing the amount of properly structured protein that is available for thyroid hormone production. The thyroid gland enlarges to compensate for decreased levels of thyroglobulin.

d. The TG gene located

Cytogenetic Location: 8q24 Molecular Location on chromosome 8: base pairs 133,879,204 to 134,147,142. The TG gene is located on the long (q) arm of chromosome 8 at position 24. More precisely, the TG gene is located from base pair 133,879,204 to base pair 134,147,142 on chromosome 8.