RGD Reference Report - Novel ENU-Induced Mutation in Tbx6 Causes Dominant Spondylocostal Dysostosis-Like Vertebral Malformations in the Rat. - Rat Genome Database

RGD Reference Report - Novel ENU-Induced Mutation in Tbx6 Causes Dominant Spondylocostal Dysostosis-Like Vertebral Malformations in the Rat. - Rat Genome Database

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Novel ENU-Induced Mutation in Tbx6 Causes Dominant Spondylocostal Dysostosis-Like Vertebral Malformations in the Rat.
Authors:	Abe, K Takamatsu, N Ishikawa, K Tsurumi, T Tanimoto, S Sakurai, Y Lisse, T Imai, K Serikawa, T Mashimo, T
Citation:	Abe K, etal., PLoS One. 2015 Jun 19;10(6):e0130231. doi: 10.1371/journal.pone.0130231. eCollection 2015.
RGD ID:	10045933
Pubmed:	PMID:26090680 (View Abstract at PubMed)
PMCID:	PMC4474719 (View Article at PubMed Central)
DOI:	DOI:10.1371/journal.pone.0130231 (Journal Full-text)
Congenital vertebral malformations caused by embryonic segmentation defects are relatively common in humans and domestic animals. Although reverse genetics approaches in mice have provided information on the molecular mechanisms of embryonic somite segmentation, hypothesis-driven approaches cannot adequately reflect human dysmorphology within the population. In a N-ethyl-N-nitrosourea (ENU) mutagenesis project in Kyoto, the Oune mutant rat strain was isolated due to a short and kinked caudal vertebra phenotype. Skeletal staining of heterozygous rats showed partial loss of the cervical vertebrae as well as hemivertebrae and fused vertebral blocks in lumbar and sacral vertebrae. In homozygous embryos, severe displacement of the whole vertebrae was observed. The Oune locus was genetically mapped to rat chromosome 1 using 202 backcross animals and 50 genome-wide microsatellite markers. Subsequently, a miss-sense mutation in the Tbx6 gene was identified in the critical region. Although the mutation is located within the T-box domain near a predicted dimmer-interface, in vitro experiments revealed that the Tbx6 variant retains normal DNA binding ability and translational efficiency. However, the variant has decreased transcriptional activation potential in response to Notch-mediated signaling. Recently, it was reported that a dominant type of familial spondylocostal dysostosis is caused by a stoploss mutation in TBX6. Thus, we propose that partial dysfunction of Tbx6 leads to similar congenital vertebral malformations in both humans and rats. The Oune strain could be a unique animal model for dominant spondylocostal dysostosis and is useful for molecular dissection of the pathology of congenital vertebral malformations in humans.

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RGD Manual Disease Annotations Click to see Annotation Detail View

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
F344-Oune/Kyo	Rat	spondylocostal dysostosis		IMP		compared to F344	RGD

Phenotype Annotations Click to see Annotation Detail View

Mammalian Phenotype

Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
F344-Oune/Kyo	Rat	abnormal lumbar vertebrae morphology		IMP		compared to F344	RGD
F344-Oune/Kyo	Rat	abnormal mating frequency		IMP		compared to F344	RGD
F344-Oune/Kyo	Rat	abnormal rib development		IMP		compared to F344	RGD
F344-Oune/Kyo	Rat	abnormal somite development		IMP		compared to F344	RGD
F344-Oune/Kyo	Rat	abnormal vertebrae development		IMP		compared to F344	RGD
F344-Oune/Kyo	Rat	cervical vertebrae degeneration		IMP		compared to F344	RGD
F344-Oune/Kyo	Rat	kinked tail		IMP		compared to F344	RGD
F344-Oune/Kyo	Rat	short tail		IMP		compared to F344	RGD

Objects Annotated

Strains

F344-Oune/Kyo (Oune)

Additional Information