|Coordinate||66,671,396 bp (GRCm38)|
|Base Change||G ⇒ A (forward strand)|
|Chromosomal Location||66,670,753-66,850,721 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] Thyroglobulin (Tg) is a glycoprotein homodimer produced predominantly by the thryroid gland. It acts as a substrate for the synthesis of thyroxine and triiodothyronine as well as the storage of the inactive forms of thyroid hormone and iodine. Thyroglobulin is secreted from the endoplasmic reticulum to its site of iodination, and subsequent thyroxine biosynthesis, in the follicular lumen. Mutations in this gene cause thyroid dyshormonogenesis, manifested as goiter, and are associated with moderate to severe congenital hypothyroidism. Polymorphisms in this gene are associated with susceptibility to autoimmune thyroid diseases (AITD) such as Graves disease and Hashimoto thryoiditis. [provided by RefSeq, Nov 2009]
PHENOTYPE: Mice homozygous for a spontaneous mutation exhibit enlarged thyroid gland, hypothyroidism, abnormal thyroid gland morphology, and decreased body weight. [provided by MGI curators]
|Amino Acid Change||Cysteine changed to Tyrosine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000070239]|
|AlphaFold||no structure available at present|
AA Change: C53Y
|Predicted Effect||probably damaging
PolyPhen 2 Score 0.999 (Sensitivity: 0.14; Specificity: 0.99)
|Meta Mutation Damage Score||0.9461|
|Is this an essential gene?||Probably nonessential (E-score: 0.129)|
|Phenotypic Category||Autosomal Recessive|
|Candidate Explorer Status||CE: excellent candidate; Verification probability: 0.931; ML prob: 0.902; human score: 5.5|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2019-09-04 9:43 PM by Diantha La Vine|
|Record Created||2016-04-05 6:18 PM|
The ito2 phenotype was identified among G3 mice of the pedigree R4487, some of which had reduced body weights compared to wild-type controls (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 38 mutations. The body weight phenotype was linked to a mutation in Tg: a G to A transversion at base pair 66,671,396 (v38) on chromosome 15, or base pair 641 in the GenBank genomic region NC_000081 encoding Tg. Linkage was found with a recessive model of inheritance, wherein three variant homozygotes departed phenotypically from 21 homozygous reference mice and 17 heterozygous mice with a P value of 2.084 x 10-8 (Figure 2).
The mutation corresponds to residue 180 in the NM_009375 mRNA sequence in exon 2 of 48 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of cysteine 53 to a tyrosine (C53Y) in the thyroglobulin protein.
|Illustration of Mutations in
Gene & Protein
Tg encodes thyroglobulin (Tg), a precursor of two thyroid hormones: 3,5,3’ triiodothyronine (T3) and 3,5,3’,5’ tetraiodothyronine (thyroxine; T4). Tg has a 20-amino acid signal peptide (amino acids 1-20). The remaining Tg protein is comprised of 11 type 1, three type 2, three type 3a, and two type 3b Cys-rich repeats followed by an acetylcholinesterase (AChE)-like domain (Figure 3) (1-3). Tg can be divided into distinct regions: region I contains the ten type I repeats between amino acids 32 and 1211 along with linker and hinge segments; region II-III contains the type 2 repeats, the type I repeat at amino acids 1510-1564, and the type 3 repeats; and the AchE-like domain (amino acids 2181-2717) (4). Within the secretory system, Tg undergoes several posttranslational modifications including glycosylation, sialylation, sulfation, phosphorylation, iodination, and formation of approximately 60 intrachain disulfide binds per monomer. Upon reaching the follicular lumen, several tyrosines are iodinated. Several of the iodinated tyrosines are coupled to form T3 and T4. The release of thyroid hormone occurs after several steps including intra-and extracellular proteolytic degradation of Tg by several proteases.
The ito2 mutation results in an cysteine to tyrosine substitution at amino acid 53. Cys53 is with the first type 1 domain, and is predicted to be involved in a disulfide bond with Cys35.
For more information about Tg, please see the record for ito.
Within the thyroid gland, epithelial cells synthesize thyroid hormones and are arranged as thyroid follicles. Between the thyroid follicles are parafollicular (alternatively, C cells), which secrete the hormone calcitonin. Tg is secreted by the thyroid cell into the follicular lumen by regulated (nonconstitutive), merocrine secretion. Upon stimulation by thyroid-stimulating hormone (TSH), Tg is reabsorbed by endocytosis/pinocytosis or phagocytosis (rodents only) to form endocytic/pinocytic vesicles or phagosomes, respectively. After release into the blood stream, T3 and T4 control metabolism. Mutations in TG have been linked to congenital goiter with hypothyroidism (euthyroidism) (OMIM: #274700) (5-7) as well as endemic and euthyroid nonendemic simple goiter (8-10). The 8q24 locus, which contains TG, is linked to autoimmune thyroid disease (AITD) including Graves’ disease and Hashimoto’s thyroiditis. Sequence analysis determined that TG is a AITD susceptibility gene in both humans and mice (11) (OMIM: #608175).
The cog/cog (Tgcog; MGI:1856829) mouse model has a point mutation in Tg that causes a Leu to Pro substitution at amino acid 2263 (12;13). The cog/cog mouse exhibits congenital hypothyroidism with goiter as well as abnormal growth, mild anemia, and defects in central nervous system development (e.g., microcephalic cerebrum with hypomyelination) (14;15). Tg expression is normal in the cog/cog mice, but the Tg protein exhibits increased proteolysis (16;17). Furthermore, the Tgcog/cog protein exhibited abnormal folding, dimerication, and export as well increased levels of several ER molecular chaperones, all of which are indicative of an ER storage defect (18). As a result, the levels of total serum T4 and T3 are low with a concomitant increase in serum TSH levels (15). A second mouse model has an ENU-induced mutation in Tg (TgR1471X; MGI:5694939). The TgR1471X mice exhibited stunted growth (19). The ito2 phenotype is similar to that of these two mouse models indicating that Tg function is impaired. Expression and localization of Tgito2 has not been examined.
1) 94°C 2:00
The following sequence of 485 nucleotides is amplified (chromosome 15, + strand):
1 aagtaaaggt gtctgtgtca ggggtgggag tggggtacgg gtgtaggact gggaggaaag
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Malthiery, Y., and Lissitzky, S. (1987) Primary Structure of Human Thyroglobulin Deduced from the Sequence of its 8448-Base Complementary DNA. Eur J Biochem. 165, 491-498.
2. Park, Y. N., and Arvan, P. (2004) The Acetylcholinesterase Homology Region is Essential for Normal Conformational Maturation and Secretion of Thyroglobulin. J Biol Chem. 279, 17085-17089.
3. Swillens, S., Ludgate, M., Mercken, L., Dumont, J. E., and Vassart, G. (1986) Analysis of Sequence and Structure Homologies between Thyroglobulin and Acetylcholinesterase: Possible Functional and Clinical Significance. Biochem Biophys Res Commun. 137, 142-148.
4. Lee, J., and Arvan, P. (2011) Repeat Motif-Containing Regions within Thyroglobulin. J Biol Chem. 286, 26327-26333.
5. Ieiri, T., Cochaux, P., Targovnik, H. M., Suzuki, M., Shimoda, S., Perret, J., and Vassart, G. (1991) A 3' Splice Site Mutation in the Thyroglobulin Gene Responsible for Congenital Goiter with Hypothyroidism. J Clin Invest. 88, 1901-1905.
6. Medeiros-Neto, G., Targovnik, H. M., and Vassart, G. (1993) Defective Thyroglobulin Synthesis and Secretion Causing Goiter and Hypothyroidism. Endocr Rev. 14, 165-183.
7. Rivolta, C. M., and Targovnik, H. M. (2006) Molecular Advances in Thyroglobulin Disorders. Clin Chim Acta. 374, 8-24.
8. Corral, J., Martin, C., Perez, R., Sanchez, I., Mories, M. T., San Millan, J. L., Miralles, J. M., and Gonzalez-Sarmiento, R. (1993) Thyroglobulin Gene Point Mutation Associated with Non-Endemic Simple Goitre. Lancet. 341, 462-464.
9. Perez-Centeno, C., Gonzalez-Sarmiento, R., Mories, M. T., Corrales, J. J., and Miralles-Garcia, J. M. (1996) Thyroglobulin Exon 10 Gene Point Mutation in a Patient with Endemic Goiter. Thyroid. 6, 423-427.
10. Gonzalez-Sarmiento, R., Corral, J., Mories, M. T., Corrales, J. J., Miguel-Velado, E., and Miralles-Garcia, J. M. (2001) Monoallelic Deletion in the 5' Region of the Thyroglobulin Gene as a Cause of Sporadic Nonendemic Simple Goiter. Thyroid. 11, 789-793.
11. Ban, Y., Greenberg, D. A., Concepcion, E., Skrabanek, L., Villanueva, R., and Tomer, Y. (2003) Amino Acid Substitutions in the Thyroglobulin Gene are Associated with Susceptibility to Human and Murine Autoimmune Thyroid Disease. Proc Natl Acad Sci U S A. 100, 15119-15124.
12. Kim, P. S., Hossain, S. A., Park, Y. N., Lee, I., Yoo, S. E., and Arvan, P. (1998) A Single Amino Acid Change in the Acetylcholinesterase-Like Domain of Thyroglobulin Causes Congenital Goiter with Hypothyroidism in the cog/cog Mouse: A Model of Human Endoplasmic Reticulum Storage Diseases. Proc Natl Acad Sci U S A. 95, 9909-9913.
13. Taylor, B. A., and Rowe, L. (1987) The Congenital Goiter Mutation is Linked to the Thyroglobulin Gene in the Mouse. Proc Natl Acad Sci U S A. 84, 1986-1990.
14. Sugisaki, T., Beamer, W. G., and Noguchi, T. (1992) Microcephalic Cerebrum with Hypomyelination in the Congenital Goiter Mouse (Cog). Neurochem Res. 17, 1037-1040.
15. Beamer, W. G., Maltais, L. J., DeBaets, M. H., and Eicher, E. M. (1987) Inherited Congenital Goiter in Mice. Endocrinology. 120, 838-840.
16. Adkison, L. R., Taylor, S., and Beamer, W. G. (1990) Mutant Gene-Induced Disorders of Structure, Function and Thyroglobulin Synthesis in Congenital Goitre (cog/cog) in Mice. J Endocrinol. 126, 51-58.
17. Basche, M., Beamer, W. G., and Schneider, A. B. (1989) Abnormal Properties of Thyroglobulin in Mice with Inherited Congenital Goiter (cog/cog). Endocrinology. 124, 1822-1829.
18. Kim, P. S., Kwon, O. Y., and Arvan, P. (1996) An Endoplasmic Reticulum Storage Disease Causing Congenital Goiter with Hypothyroidism. J Cell Biol. 133, 517-527.
19. Andrews, T. D., Whittle, B., Field, M. A., Balakishnan, B., Zhang, Y., Shao, Y., Cho, V., Kirk, M., Singh, M., Xia, Y., Hager, J., Winslade, S., Sjollema, G., Beutler, B., Enders, A., and Goodnow, C. C. (2012) Massively Parallel Sequencing of the Mouse Exome to Accurately Identify Rare, Induced Mutations: An Immediate Source for Thousands of New Mouse Models. Open Biol. 2, 120061.
|Science Writers||Anne Murray|
|Authors||William McAlpine and Bruce Beutler|