A novel compound heterozygous mutation in the thyroglobulin gene resulting in congenital goitrous hypothyroidism with high serum triiodothyronine levels

Abstract

A novel compound heterozygous mutation in the thyroglobulin gene resulting in congenital goitrous hypothyroidism with high serum triiodothyronine levels Abstract Thyroglobulin abnormality is a rare cause of congenital hypothyroidism and only a limited number of mutations in the thyroglobulin gene have been reported. We analyzed the thyroglobulin gene in a patient with congenital goitrous hypothyroidism. This girl was identified with hyperthyrotropinemia in a neonatal mass-screening test. The patient had goiter, and her body weight gain was poor. Distal femoral epiphysis was absent on roentgenography. Her serum thyroxine level was low; however, her triiodothyronine level was high. Autoantibodies against triiodothyronine, thyroid peroxidase, and thyroglobulin were all negative. Her serum thyroglobulin level was undetectable. The thyroglobulin gene from the genomic DNA of the patient was analyzed by direct sequencing. Two novel heterozygous missense mutations, Cys1897Tyr (exon 31) and Arg2336Gln (exon 40), were found in the patient. The former mutation was derived from her mother, suggesting a compound heterozygous state. Normal triiodothyronine and low thyroxine concentrations are often observed in patients with thyroglobulin gene mutations. We considered that some patients with thyroglobulin abnormality might have high triiodothyronine levels. In cases of congenital goitrous hypothyroidism with normalto-high triiodothyronine levels and low serum thyroglobulin levels, thyroglobulin abnormality should be considered.

Cis and Trans Actions of the Cholinesterase-like Domain within the Thyroglobulin Dimer

“…The major hormone-forming site in Tg resides in the first 130 residues of the mature protein, yet homozygous (or compound heterozygous) mutations in the carboxyl-terminal ChEL domain result in a devastating impact on thyroid hormone formation (15)(16)(17)(18)(19). All evidence points to the notion that such Tg mutants exhibit impaired secretion (28).…”

“…The ChEL domain is a commonly affected site of mutation in human congenital hypothyroidism with deficient Tg, including the recently described A2215D (15,16), R2223H (17), G2300D, R2317Q (18), G2355V, and G2356R and the skipping of exon 45 (which normally encodes 36 amino acids), as well as the Q2638stop mutant (19). Additionally, the homozygous Tg-G2300R mutation in the ChEL domain (equivalent to residue 2298 of mature mouse Tg) is responsible for congenital hypothyroidism in rdw/rdw rats (20,21), whereas the Tg-L2263P point mutation is responsible for congenital hypothyroidism in the cog/cog mouse (22).…”

The cholinesterase-like domain of thyroglobulin functions as an intramolecular chaperone

“…In all 3 species, the cellular phenotype described includes a dilated ER with induction of ER molecular chaperones (14), activation of ER stress signaling pathways (15), and ER-associated degradation (ERAD) of most of the mutant Tg gene product (16). Of the cases (and animal models) published to date, the cholinesterase-like (ChEL) domain is a very commonly affected site, involving mutations including the newly described A2215D (17,18); R2223H (19); G2300D,R2317Q (20); G2355V,G2356R; or the skipping of exon 45 (normally encoding 36 residues of the ChEL domain); as well as Q2638Z mutants (where Z represents stop) (21). In addition are polymorphisms including P2213L and W2482R; and R2511Q that may be associated with an increased incidence of nonmedullary thyroid cancer (22).…”

The Cholinesterase-like Domain, Essential in Thyroglobulin Trafficking for Thyroid Hormone Synthesis, Is Required for Protein Dimerization

“…In human congenital hypothyroidism with deficient Tg, the ChEL domain is a commonly affected site of mutation, including the recently described A2215D (20,21), R2223H (22), G2300D, R2317Q (23), G2355V, G2356R, and the skipping of exon 45 (which normally encodes 36 amino acids), as well as the Q2638stop mutant (24) (in addition to polymorphisms including P2213L, W2482R, and R2511Q that may be associated with thyroid overgrowth (25)). As best as is currently known, all of the congenital hypothyroidism-inducing Tg mutants are defective for intracellular transport (26).…”