129S(Cg)-Tgfbr2^tm1.1Hcd/J

Stock number: 024634
Research areas: Cardiovascular Research, Developmental Biology Research, Internal/Organ Research

Description

This Tgfbr2 G357W mutant strain recapitulates vascular and skeletal features of Loeys-Dietz Syndrome (LDS).

Detailed description

Loeys-Dietz Syndrome (LDS) is a connective tissue disorder that is characterized by a high risk for aneurysm and dissection throughout the arterial tree and phenotypically resembles Marfan Syndrome. LDS is caused by heterozygous missense mutations in either TGF receptor gene (TGFBR1 or TGFBR2).

This targeted mutant strain carries an G357W missense mutation associated with LDS in the mouse Tgfbr2 (transforming growth factor, beta receptor II) gene. Mutant and wildtype alleles are expressed approximately equally in the aortic walls of heterozygotes. Heterozygous mice develop progressive aortic root aneurysm, as well as elongation and tortuosity of the aortic arch and coronary arteries. A subtle but significant deviation from the wildtype condition is detectable at 4 weeks of age, and becomes highly reproducible and dramatic at 24 weeks. At 24 weeks of age, elastic fiber fragmentation is detectable in the aortic roots of these knockin mice. The aortic wall also shows progressive thickening with excessive collagen deposition. Approximately 10-15% of heterozygotes may die by 180 days of age due to aortic dissection. Hemothorax or hemopericardium is observable in approximately 60% of deaths. These mice also develop skeletal manifestations associated with LDS, such as kyphosis, overgrowth of the ribs and craniosynostosis.

Development

Site-directed mutagenesis was performed to substitute glycine 357 with tryptophan (GGC->TGG; guanine to thymine and cytosine to guanine at nucleotides 1069 and 1071 respectively) in exon 4 of the targeted gene. A loxP-flanked neomycin selection cassette was placed in intron 3. Linearized targeting vector was introduced to 129S6/SvEvTac-derived embryonic stem (ES) cells. Chimeric offspring were mated to C57BL/6J. The loxP-flanked neomycin cassette was removed by mating animals with a CAG-Cre strain. Animals were backcrossed to 129S6/SvEvTac for at least 10 generations by the donating lab.

Allele

Symbol: Tgfbr2^tm1.1Hcd
Name: targeted mutation 1.1, Harry C Dietz
MGI accession ID: MGI:5543796
Generation method: Targeted
Marker symbol: Tgfbr2
Marker name: transforming growth factor, beta receptor II
Chromosome: 9
Strain of origin: 129S6/SvEvTac
Molecular note: Site-directed mutagenesis was performed to substitute glycine 358 with tryptophan (GGC->TGG; guanine to thymine and cytosine to guanine at nucleotides 1069 and 1071 respectively) in exon 4 of the targeted gene. A loxP-flanked neomycin selection cassette was placed in intron 3. Cre-mediated recombination removed the floxed neo cassette.