| First Author | Dionne LA | Year | 2014 |
| Journal | MGI Direct Data Submission | Mgi Jnum | J:213054 |
| Mgi Id | MGI:5582767 | Citation | Dionne LA, et al. (2014) The hypothyroid 2 Jackson mutation. MGI Direct Data Submission |
| abstractText | The recessive spontaneous mutation hypothyroid 2 Jackson (Tshr<hyt-2J>) was identified in a B6129PF2/J mouse at The Jackson Laboratory in 2006 due to the much smaller body size. The weight of homozygotes is approximately 60-70% that of heterozygotes. Homozygotes have a normal life span, and will breed if left with the mother to mature until they are 12-18 weeks old. This mutation does not cause circling. The mode of inheritance of this mutation was established by outcrossing a mutant to 129P3/J. None of their offspring were small, but when these normal F1 animals were intercrossed they produced both small and normal sized pups in the expected Mendelian ratio proving that this mutation is recessive, fully penetrant, and does not cause significant embryonic lethality in heterozygous dams. Allele tests with Duox2<thyd> and Tpo<tee> each produced all normal offspring. To determine the chromosomal location of the mutation, homozygous mutant mice were mated to CAST/EiJ males. The F1 progeny were intercrossed and linkage analysis mapped this mutation to an interval between D12Mit6 (90.0 Mb) and D12Mit262 (110 Mb). Because of the phenotype and map location an allele test was done with B6;129S1-Tshr<tm1Rmar>/J heterozygotes and 5 of 14 pups had the small phenotype. Sanger sequencing identified a C to T transition in Chromosome 12 at position 91,537,844. This is in exon 10 of the thyroid stimulating hormone receptor (Tshr) gene and results in a premature stop codon and a predicted loss of the transmembrane portion of TSHR. Both male and female homozygotes assessed at 3 weeks of age showed serum thyroxine (T4) levels below 0.3 ug/dl where unaffected (+/?) littermates showed an average of 6.9 ug/dl, with the values ranging from 4.8 to 10 ug/dl in 21 mice. A T4 level below 0.3 ug/dl persisted in homozygotes at 8 weeks of age. A routine pathological screen identified hyperplasia of the pituitary cells that produce thyroid stimulating hormone and in the thyroid the follicular epithelium was very thin with little cytoplasm, although the thyroid was not abnormally small. Although the size of the thyroid was normal, there were many empty follicles. One homozygous female at 13 weeks of age was noted to have very pale dermis when the skin was pulled back, one homozygous female at 41 weeks of age had myocardial degeneration and B cell follicles in the thymus, and one homozygous male at 3 weeks of age had teeth that had not yet erupted, but x-rays of two more 3-week-old homozygous males failed to find any skeletal abnormalities or failed eruption of teeth. The eyes of six mutants and three controls were examined by ophthalmoscopy at 48 days of age and appeared normal. However, electroretinography detected low b-wave and low cone amplitude in one of these homozygotes and there were similar findings in one homozygous male at 15 weeks of age, and 2 homozygotes at 37 weeks of age, while 2 homozygotes assessed at 8 weeks of age had only low cone amplitude. Auditory Brainstem Response was assessed and hearing impairment was found in 3 of 4 homozygotes at 98 days of age, in all three homozygotes assessed at 43 days of age, and in only 1 of 4 homozygotes assessed at 42 days of age. Reviewing the pedigree of the assessed mice, the data showed greater hearing loss in pups born from a homozygous mother than those born from a heterozygous mother. This is consistent with previous reports from Sprenkle at al. studying the hearing loss associated with in utero T4 depletion. The authors thank Lisa DeLaittre for discovering the mutant, Coleen Kane for histological preparation, Bo Chang and Norman Hawes for eye examinations and Chantal Longo-Guess for ABR testing. |
