Genetics and phenomics of hypothyroidism and goiter due to thyroglobulin mutations

Thyroglobulin (TG) defects due to TG gene mutations have an estimated incidence of approximately 1 in 100,000 newborns. This dyshormonogenesis displays a wide phenotype variation and is characterized usually by: the presence of congenital goiter or goiter appearing shortly after birth, high 131I uptake, negative perchlorate discharge test, low serum TG and elevated serum TSH with simultaneous low serum T4 and low, normal or high serum T3. Mutations in TG gene have been also reported associated with endemic and euthyroid nonendemic simple goiter. TG gene defects are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous for mutations. Up to now, 50 mutations have been identified and characterized in the human TG: 23 missense mutations, 10 nonsense mutations, 5 single and 1 large nucleotide deletions, 1 single nucleotide insertion and 10 splice site mutations. The functional consequences of this mutations could be structural changes in the protein molecule that alter the normal protein folding, assembly and biosynthesis of thyroid hormones, leading to a marked reduction in the ability to export the protein from the endoplasmic reticulum.