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Mutat Res. 2014 Apr;762:17-23. doi: 10.1016/j.mrfmmm.2014.02.003. Epub 2014 Feb 28.

A novel mutation in the thyroglobulin gene that causes goiter and dwarfism in Wistar Hannover GALAS rats.

Author information

1
Toxicology Division, Institute of Environmental Toxicology, 4321 Uchimoriya-machi, Joso, Ibaraki 303-0043, Japan.
2
Technology and Development Team for Mammalian Genome Dynamism, RIKEN BioResource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
3
Safety Research Division, Safety Research Institute for Chemical Compounds Co., Ltd., 363-24 Shin-ei, Kiyota-ku, Sapporo, Hokkaido 004-0839, Japan.
4
Toxicology Division, Institute of Environmental Toxicology, 4321 Uchimoriya-machi, Joso, Ibaraki 303-0043, Japan. Electronic address: aoyama@iet.or.jp.

Abstract

Outbred stocks of rats have been used extensively in biomedical, pharmaceutical and/or toxicological studies as a model of genetically heterogeneous human populations. One of such stocks is the Wistar Hannover GALAS rat. However, the colony of Wistar Hannover GALAS rat has been suspected of keeping a problematic mutation that manifests two distinct spontaneous abnormalities, goiter and dwarfism, which often confuses study results. We have successfully identified the responsible mutation, a guanine to thymine transversion at the acceptor site (3' end) of intron 6 in the thyroglobulin (Tg) gene (Tgc.749-1G>T), that induces a complete missing of exon 7 from the whole Tg transcript by mating experiments and subsequent molecular analyses. The following observations confirmed that Tgc.749-1G>T/Tgc.749-1G>T homozygotes manifested both dwarfism and goiter, while Tgc.749-1G>T/+ heterozygotes had only a goiter with normal appearance, suggesting that the mutant phenotypes inherit as an autosomal semi-dominant trait. The mutant phenotypes, goiter and dwarfism, mimicked those caused by typical endocrine disrupters attacking the thyroid. Hence a simple and reliable diagnostic methodology has been developed for genomic DNA-based genotyping of animals. The diagnostic methodology reported here would allow users of Wistar Hannover GALAS rats to evaluate their study results precisely by carefully interpreting the data obtained from Tgc.749-1G>T/+ heterozygotes having externally undetectable thyroidal lesions.

KEYWORDS:

Acceptor site; Intron; Outbred; Reproduction study; Splicing abnormality; Thyroid

PMID:
24582622
DOI:
10.1016/j.mrfmmm.2014.02.003
[Indexed for MEDLINE]

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