Thyroglobulin Gene Mutations in Congenital Hypothyroidism

Abstract

Human thyroglobulin (TG) gene is a single copy gene, 270 kb long, that maps on chromosome 8q24.2–8q24.3 and contains an 8.5-kb coding sequence divided into 48 exons. TG is exclusively synthesized in the thyroid gland and represents a highly specialized homodimeric glycoprotein for thyroid hormone biosynthesis. Mutations in the TG gene lead to permanent congenital hypothyroidism. The presence of low TG level and also normal perchlorate discharge test in a goitrous individual suggest a TG gene defect. Until now, 52 mutations have been identified and characterized in the human TG gene with functional impact such as structural changes in the protein that alter the normal protein folding, assembly and biosynthesis of thyroid hormones. 11 of the mutations affect splicing sites, 11 produce premature stop codons, 23 lead to amino acid changes, 6 deletions (5 single and 1 involving a large number of nucleotides) and 1 single nucleotide insertion. TG mutations are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous. The p.R277X, p.C1058R, p.C1977S, p.R1511X, p.A2215D and p.R2223H mutations are the most frequently identified TG mutations. This mini-review focuses on genetic and clinical aspects of TG gene defects.

Importance of molecular genetic analysis in the diagnosis and classification of congenital hypothyroidism

“…Genetic abnormalities in any of the key thyroid proteins can produce CH [3,4]. Based on genetic alterations, the CH can be classified into two main groups: (i) those caused by disorders of thyroid gland development (dysembriogenesis or dysgenesis), which accounts for 80-85 % of cases; and (ii) by defects in any step of thyroid hormone synthesis (dyshormonogenesis), which accounts for remaining 15-20 % of cases [3,4].…”

“…Based on genetic alterations, the CH can be classified into two main groups: (i) those caused by disorders of thyroid gland development (dysembriogenesis or dysgenesis), which accounts for 80-85 % of cases; and (ii) by defects in any step of thyroid hormone synthesis (dyshormonogenesis), which accounts for remaining 15-20 % of cases [3,4]. Thyroid dysembryogenesis results from a thyroid gland that is completely absent in orthotopic or ectopic location (agenesis or athyreosis), severely reduced in size but in the proper position in the neck (orthotopic hypoplasia) or located in an unusual position (thyroid ectopy) at the base of the tongue or along the thyroglossal tract [4]. In a very minority of these patients (5 %), the CH is associated with mutations in genes responsible for the development or growth of thyroid follicular cells: NKX2.1 FOXE1, PAX-8, NKX2.5, and TSHR genes [3,4].…”

“…Thyroid dysembryogenesis results from a thyroid gland that is completely absent in orthotopic or ectopic location (agenesis or athyreosis), severely reduced in size but in the proper position in the neck (orthotopic hypoplasia) or located in an unusual position (thyroid ectopy) at the base of the tongue or along the thyroglossal tract [4]. In a very minority of these patients (5 %), the CH is associated with mutations in genes responsible for the development or growth of thyroid follicular cells: NKX2.1 FOXE1, PAX-8, NKX2.5, and TSHR genes [3,4]. Consequently, the molecular mechanisms underlying the defect in thyroid organogenesis in the great majority of cases remain to be elucidated.…”

“…Consequently, the molecular mechanisms underlying the defect in thyroid organogenesis in the great majority of cases remain to be elucidated. In contrast, thyroid dyshormonogenesis has been linked in more than 90 % of cases to mutations in the sodium iodide symporter (NIS), SLC26A4 (which encodes pendrin), thyroperoxidase (TPO), dual oxidase 2 (DUOX2), DUOX maturation factor 2 (DUOX-A2), dehalogenase 1 (DEHAL1), and thyroglobulin (TG) genes [3,4]. These mutations produce a heterogeneous spectrum of congenital goitrous hypothyroidism, usually transmitted in an autosomal recessive mode.…”

Against all odds: blended phenotypes of three single-gene defects

“…Recessive TG mutations are a known cause of congenital thyroid dyshormonogenesis (MIM #274700). 15 TG is a large gene producing many alternatively spliced transcripts. 16 Mutations affecting splice sites make up a significant portion of all reported pathogenic TG variants.…”