Human TSHR A-subunit targeted to (and expressed in) the thyroid gland by the bovine thyroglobulin promoter. The original transgenics were generated in BALB/c and have been backcrossed to NOD.H2h4.

Homozygous: Not studied

Hemizygous: Undetermined

These mice spontaneously produce pathogenic TSHR antibodies which are the direct cause of Graves’ disease in humans. 

1) This strain carries the same mutation as C.Cg-Tg(TG-TSHR)51.9Smcl/Mmucd, MMRRC:014125 mice that express the human thyrotropin receptor (TSHR) A-subunit at low levels in the thyroid gland (1,2). This strain is on the BALB/c background. Males of this strain were bred to female NOD.H2h4 mice [NOD.Cg-H2h4/DilTacUmmJ to generate N1. 3) Male N1 offspring bearing the “51.9" transgene were backcrossed to female NOD.H2h4 mice to generate N2. 4)To introduce the NOD.H2h4 Y chromosome, N4 positive females were crossed to NOD.H2h4 males. Thereafter, male transgenics were bred to NOD.H2h4 females. 5) Males with the highest percentage of NOD.H2h4 genes (analyzed by Jackson Labs) were used when possible (sometimes the “best” male was aggressive and could not be used for breeding). At N6, three males had 99% NOD.H2h4 genes and we used for breeding. 6) We are currently generating N10 mice. The offspring will be heterozygous and will be maintained by crossing male transgenics to NOD.H2h4 females. Offspring from these crosses (from N2 to N8) “hTSHR/NOD-H2h4 mice” spontaneously produce pathogenic TSHR antibodies which are the direct cause of Graves’ disease in humans. Notes: Graves’ disease is one of the commonest autoimmune diseases in humans; approximately 1% of the population will develop Graves’ disease in their lifetime. No animals other than humans generate TSHR antibodies spontaneously, not even our closest relatives the great apes (3). Consequently, this transgenic mouse is the first animal model that spontaneously produces TSHR antibodies and can be investigated for novel immune approaches to suppress TSHR antibody production with the potential to develop novel therapies to cure Graves’ disease in humans. Our data were presented as one of four selected “Highlighted Orals” at the 84th Annual Meeting of the American Thyroid Association on October 30 in San Diego (4). References 1. Pichurin, P. N., C.-R. Chen, G. D. Chazenbalk, H. Aliesky, N. Pham, B. Rapoport, and S. M. McLachlan. 2006. Targeted expression of the human thyrotropin receptor A-subunit to the mouse thyroid: Insight into overcoming the lack of response to A-subunit adenovirus immunization. J Immunol. 176:668-676. 2. McLachlan, S. M., Y. Nagayama, P. N. Pichurin, Y. Mizutori, C. R. Chen, A. Misharin, H. A. Aliesky, and B. Rapoport. 2007. The link between Graves' disease and Hashimoto's thyroiditis: A role for regulatory T cells. Endocrinol. 148:5724-5733. 3. Aliesky, H., C. L. Courtney, B. Rapoport, and S. M. McLachlan. 2013. Thyroid autoantibodies are rare in nonhuman great apes and hypothyroidism cannot be attributed to thyroid autoimmunity. Endocrinol. 154:4896-4907. 4. McLachlan, S. M., Aliesky, H., Banuelos, B., and Rapoport, B. 2014. Development of a unique mouse model for Graves' disease that spontaneously develops pathogenic TSH receptor antibodies. 84th Annual Meeting of the American Thyroid Association October 29-November 2, 2014 , 87. 2014 (Abstract)

Wild-type littermates

The MMRRC Centers have developed a genetic QC pipeline using MiniMUGA array genotyping to provide additional information on strain backgrounds for MMRRC congenic and inbred strains. For more information on when data may be available, or to request genotyping for a strain of interest, please contact mmrrc@missouri.edu. Older strains may not have this information.

Sandra M McLachlan, Ph.D., Cedars-Sinai Medical Center & University of California, Los Angeles.

McLachlan SM, Aliesky H, Banuelos B, and Rapoport B. Development of a unique mouse model for Graves' disease that spontaneously develops pathogenic TSH receptor antibodies. 84th Annual Meeting of the American Thyroid Association October 29-November 2, 2014 , 87. 2014 (presentation)
Pichurin PN, Chen CR, Chazenbalk GD, Aliesky H, Pham N, Rapoport B, and McLachlan SM. Targeted expression of the human thyrotropin receptor A-subunit to the mouse thyroid: Insight into overcoming the lack of response to A-subunit adenovirus immunization. J Immunol. 2006 Jan 1;176(1):668-76. (Medline PMID:16365463)
McLachlan SM, Nagayama Y, Pichurin PN, Mizutori Y, Chen CR, Misharin A, Aliesky HA, and Rapoport B. The link between Graves' disease and Hashimoto's thyroiditis: A role for regulatory T cells. Endocrinology. 2007 Dec;148(12):5724-33. Epub 2007 Sep 6. (Medline PMID:17823263)

Aliesky H, Courtney CL, Rapoport B, and McLachlan SM. Thyroid autoantibodies are rare in nonhuman great apes and hypothyroidism cannot be attributed to thyroid autoimmunity. Endocrinology. 2013 Dec;154(12):4896-907. Epub 2013 Oct 3. (Medline PMID:24092641)