title: Novel ENU-Induced Mutation in Tbx6 Causes Dominant Spondylocostal Dysostosis-Like Vertebral Malformations in the Rat.
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 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.
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Abe
authors.affiliation: Department of Biosciences, School of Science, Kitasato University, Sagamihara, Kanagawa, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Takamatsu
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tsurumi
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Tanimoto
authors.affiliation: Department of Biosciences, School of Science, Kitasato University, Sagamihara, Kanagawa, Japan.
authors.forename: Yukina
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lisse
authors.affiliation: MDI Biological Laboratory, Davis Center for Regenerative Biology and Medicine, Bar Harbor, Maine, United States of America.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lisse
authors.affiliation: Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Imai
authors.affiliation: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Serikawa
authors.affiliation: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tomoji
authors.initials: T
authors.lastname: Mashimo
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000009:adverse effects; D005260:Female; D005786:Gene Expression Regulation; D023061:Gene Order; D005799:Genes, Dominant; D056426:Genetic Loci; D005838:Genotype; D006548:Hernia, Diaphragmatic / Q000235:genetics* / Q000473:pathology*; D008297:Male; D009154:Mutation / Q000187:drug effects; D010641:Phenotype; D051381:Rats; D016415:Sequence Alignment; D013131:Spine / Q000002:abnormalities*
chemical_list: D005038:Ethylnitrosourea