Homozyous Sgcb (sarcoglycan, beta (dystrophin-associated glycoprotein) targeted mutant mice develop severe muscular dystrophy and cardiomyopathy with focal areas of necrosis.
Kevin Campbell, University of Iowa
Homozyous mice are viable and fertile. They develop severe muscular dystrophy and cardiomyopathy with focal areas of necrosis. Severe dystrophic changes including necrosis, dystrophic calcification, fatty infiltration, central nucleation, fibrosis, atrophy and hypertrophy are detected in diaphragm and calf/thigh muscle. Some of these changes occur in 4-week-old animals and accumulate with age. At 20 weeks of age, several regions of focal myocardial necrosis have been observed; small areas of necrotic myocardiocytes may be observed as early as 9 weeks of age. At 30 weeks of age, large areas of fibrosis are detected. Sarcoglycan-sarcospan and dystroglycan complexes are disrupted in skeletal, cardiac, and smooth muscle membranes. Loss of the sarcoglycan-sarcospan complex in vascular smooth muscle results in vascular irregularities in heart, diaphragm, and kidneys. Vascular constrictions in skeletal muscle, cardiac muscle and kidneys is observed. Epsilon-sarcoglycan (SGCE) is also reduced in membrane preparations of striated and smooth muscle. The muscular dystrophy phenotype is reportedly more severe on the 129 background than the C57BL/6 background. Northern blot analysis of skeletal muscle with an exon 6 probe reveals no transcript in the skeletal muscle of homozygous mice. This mutant mouse strain represents a model that may be useful in studies of muscular dystrophy, cardiomyopathy, and smooth muscle dysfunction.
A targeting vector containing a neomycin resistance gene was used to replace exons 3-6 of the gene. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-Kitl+-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The donating investigator reported that chimeric animals were backcrossed with C57BL/6 (see SNP note below) five times.
A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, 1 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.
|Allele Name||targeted mutation 1, Kevin P Campbell|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Sgcb, sarcoglycan, beta (dystrophin-associated glycoprotein)|
|Strain of Origin||(129X1/SvJ x 129S1/Sv)F1-Kitl+|
|Molecular Note||A loxP flanked neomycin cassette replaced a genomic fragment that contained exons 3-6. These exons encode part of the transmembrane domain and the extracellular portion of the protein. Northern blot analysis revealed that no transcript was detectable in skeletal muscle of homozygous mice and Western blot and immunohistochemical analysis demonstrated that the protein was absent in the sarcolemma of skeletal muscle derived from homozygous mice.|
|Mutations Made By|| |
Kevin Campbell, University of Iowa
When maintaining a live colony, homozygotes are intercrossed. Mice with decreased mobility may benefit from ground grain placed in the bottom of the cage.
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