Compound Heterozygous Mutations in the Thyroglobulin Gene (1143delC and 6725G→A [R2223H]) Resulting in Fetal Goitrous Hypothyroidism

Abstract

In a 22-yr-old healthy woman, a fetal goiter was diagnosed coincidentally by ultrasound during the sixth month of gestation, and hypothyroidism was affirmed by a high TSH (336 mU/liter) concentration after cordocentesis. A second ultrasound examination at 27 wk gestation showed further enlargement of the goiter (34/21 mm). Two intraamniotic injections of 200 microg levothyroxine were performed during the seventh month of pregnancy. Ultrasound studies revealed a fetal goiter size of 30/18 mm during the eighth month of gestation. The woman delivered at term a female infant with an Apgar score of 10 at 1 and 5 min. Cord blood analysis indicated elevated TSH (284 mU/liter) and low free T(4) (5.5 pmol/liter) levels. The serum thyroglobulin (Tg) concentration was low (0.8 ng/ml), whereas ultrasound of the neonate indicated an enlarged thyroid gland (32/15/14 mm). During the second pregnancy, ultrasound examination revealed a goiter, and fetal hypothyroidism was also confirmed after umbilical vein blood sampling (TSH, 472 mU/liter). After two intraamniotic injections of 500 microg levothyroxine, the woman delivered a male infant at 37 wk of pregnancy. In cord blood the serum TSH concentration was 39 mU/liter, and the serum Tg level was low (0.7 ng/ml). The parents were nonconsanguineous. After birth of the two affected siblings, genomic DNA sequencing identified the presence of compound heterozygous mutations of the Tg gene: the paternal mutation consists of a cytosine deletion at nucleotide 1143 in exon 9 (1143delC), resulting in a frameshift that generates a stop codon at position 382, and the maternal mutation is a guanine to adenine substitution at position 6725 in exon 38, creating the R2223H missense mutation in the acetylcholinesterase homology domain of Tg. In conclusion, we report two siblings with congenital goiter and hypothyroidism caused by compound heterozygous mutations of the Tg gene.

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).…”

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

“…A missense mutation in this domain in congenital goitrous hypothyroidism cog/cog mice leads to the retention of thyroglobulin within the endoplasmic reticulum (Kim et al 1998). There are also reports of missense mutations in this domain in humans and in rdw rats (Caron et al 2003;Hishinuma et al 2000). There are three types of repetitive units in the thyroglobulin protein, and residue Cys1897 is located in repeated motif type 3a (Malthiery and Lissitzky 1987).…”

“…The prevalence of patients with thyroglobulin defects is 1:40,000-100,000 newborns. However, due to the difficulty of analyzing large genes, only nine different mutations leading to congenital goiter and hypothyroidism have thus far been identified in the human thyroglobulin gene (Ieiri et al 1991;Targovnik et al 1993Targovnik et al , 1995van de Graaf et al 1999;Hishinuma et al 1999;Caron et al 2003;Gutnisky et al 2004).…”