These MgR mice show under-expression of fibrillin-1 leading to Marfan syndrome-likemanifestations.
Francesco Ramirez, Mount Sinai Hospital
Both heterozygous and homozygous "mgR" mutant mice are viable with no phenotypic abnormalities at birth. The protein expressed from this mutant allele is the same size as wild-type. Skin tissues show an intermediate reduction in transcript levels compared to wild-type and the mg-delta null allele. Thus the "mgR" mutation does not completely ablate gene function (resulting in rapid death). Instead, expression is hypomorphic and conducive to studying the clinical stages precursive to animal lethality. Homozygotes develop medial calcification, the inflammatory-fibroproliferative response, and inflammation-mediated elastolysis in the natural history of dissecting aneurysm and die between 2-6 month of age with Marfan syndrome (MFS)-like manifestations.
A targeting vector containing a PGKneo cassette was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. An unequal crossover event inserted the PGKneo-cassette between exons 18 and 19 of the endogenous gene, resulting in no loss of endogenous sequence for this "mgR" mutant allele. Interestingly, a 67 bp long A/T-rich stretch of DNA was found to have been added at the point of transition between introns 24 and 18. Targeted ES cells were injected into C57BL/6 blastocysts and the resulting chimera's were bred to C57BL/6 mice to establish heterozygous mutants. Heterozygotes were backcrossed to C57BL/6 mice for 10 generations and then maintained by breeding heterozygotes together for many generations prior to arrival at The Jackson Laboratory.
|Allele Name||targeted mutation 2, Francesco Ramirez|
|Allele Type||Targeted (Hypomorph)|
|Allele Synonym(s)||Fbn1mgR; mgR|
|Gene Symbol and Name||Fbn1, fibrillin 1|
|Gene Synonym(s)||ACMICD; AI536462; ECTOL1; FBN; Fib-1; GPHYSD2; MASS; MFS1; OCTD; SGS; SSKS; Tsk; WMS; WMS2; expressed sequence AI536462; tight skin|
|Strain of Origin||(129X1/SvJ x 129S1/Sv)F1-Kitl<+>|
|Molecular Note||An unequal crossover event resulted in the insertion of a neomycin selection cassette into intron 18 with no loss of coding sequences. RT-PCR analysis confirmed that correctly spliced transcripts are produced from this allele. Northern blot analysis onmRNA derived from skin samples of homozygous mice demonstrated that transcript expression was reduced approximately five-fold. Immunoprecipitation experiments on fibroblasts isolated from homozygous mice confirmed that a protein was expressed from this allele at reduced levels compared to wild-type. This is a hypomorphic allele.|
|Mutations Made By|| |
Francesco Ramirez, Mount Sinai Hospital
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