Advances and Perspectives in Genetics of Congenital Thyroid Disorders Associated with Thyroglobulin Gene Mutations

Dyshormonogenesis due to thyroglobulin (TG) gene mutations is a rare cause of congenital hypothyroidism with an estimated incidence of approximately 1 in 100,000 newborns. The TG gene is organized in 48 exons, spanning over 270 kb on human chromosome 8q24. The human TG mRNA is 8.5 Kb long and the preprotein monomer is composed of a 19 amino acids signal peptide followed by a 2749 residues polypeptide. Until now, one hundred seventeen deleterious mutations in the human TG gene have been identifi ed and characterized, originating structural changes in the protein that alter the normal protein folding, assembly and biosynthesis of thyroid hormones: 19 splice site mutations, 23 nonsense mutations, 57 missense mutations, 13 deletions (9 single nucleotide deletions, 2 multiple nucleotide deletions and 2 involving a large number of nucleotides), 4 single nucleotide insertions or duplication and 1 imperfect DNA inversion. The p.R277*, p.R1511*, p.A2215D, p.R2223H and p.R2317* mutations are the most frequently identifi ed TG mutations in Caucasian population, whereas c.274+2T>G, p.C1058R, p.C1245R and p.C1977S are the most common mutations in Asian population. TG mutations are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous for gene mutations and the parents should be carriers of one the TG mutation. New approaches including the use of new sequencing technology, will eclipse traditional methods of detecting mutations and will allow the quick identifi cation of mutations in remote regions as well as the detection of coexistence of multiple mutations in the same gene or in different thyroid genes.