Novel ENU-induced mutation in Tbx6 causes dominant spondylocostal dysostosis-like vertebral malformations in the rat

Koichiro Abe, Nobuhiko Takamatsu, Kumiko Ishikawa, Toshiko Tsurumi, Sho Tanimoto, Yukina Sakurai, Thomas Lisse, Kenji Imai, Tadao Serikawa, Tomoji Mashimo

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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 Tbox 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.

Original languageEnglish (US)
Article numbere0130231
JournalPloS one
Volume10
Issue number6
DOIs
StatePublished - Jun 19 2015
Externally publishedYes

ASJC Scopus subject areas

  • General

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