Ryr1AG mutant mice carry an ENU-induced point mutation which causes muscle weakness in heterozygotes and postnatal lethality in homozygotes.
Lee Niswander, University of Colorado, Denver
Ryr1 belongs to a family of proteins that create channels for the controlled release of calcium ions from stores within cells. Myopathies due to mutations in RYR1 (ryanodine receptor 1, skeletal muscle) are inherited and currently incurable.
These Ryr1AG mutant mice carry an ENU-induced missense point mutation which creates an A12864G change in exon 93, outside of the channel region of Ryr1. Homozygous mutants can be identified by a lack of embryonic motor movement and die shortly after birth from cyanosis due to lack of contraction of the diaphragm muscle.
Heterozygotes, used as a model for muscle myopathy, exhibit muscle weakness associated with a leak of potassium from the cells. One-month, two-month, and one-year old heterozygous mice show a significant decrease in grip strength and considerable deficits on a wire hanging task compared to wildtype mice. Analysis of vastus lateralis, adductor magnus and soleus muscles reveals centrally located nuclei, core-like structures, and decreased COS and NADH-TR staining, whereas no cores are observed in wildtype muscle. The RyrAG mutation is also associated with a defect in calcium release and mitochondrial dysfunction in skeletal muscle. Potassium homeostasis is disrupted, but this myopathy can be rescued by increasing potassium through diet or FDA-approved drugs (e.g. the angiotensin-converting enzyme (ACE) inhibitor, Enalapril).
ENU mutagenesis was performed on male C57BL/6J mice which were subsequently crossed with 129S1/SvImJ females. G3 embryos were screened at embryonic day 18.5 (E18.5) for recessive mutations that affected embryonic locomotion. The mutation in Line1-4, exhibiting heterozygous muscle weakness and homozygous embryonic immotility, was mapped and sequenced, revealing an A12864G (protein NP_033135, resulting in E4242G) mutation in exon 9 of the mouse Ryr1 gene. This strain was backcrossed to 129S1/SvImJ for more than 10 generations by the donating lab.
|Allele Name||mutation 1, Lee Niswander|
|Allele Type||Chemically induced (ENU)|
|Gene Symbol and Name||Ryr1, ryanodine receptor 1, skeletal muscle|
|Strain of Origin||C57BL/6J|
|Molecular Note||This mutation was isolated in an ENU-mutagenesis screen. The molecular mutation is an A-to-G point mutation in the coding region of the gene. Transcript accession for RyR1 was NM_0091009 and the ENU-induced change was A12864G (protein NP_033135, resulting in E4242G).|
Heterozygotes are viable, fertile, and demonstrate a level of myopathy that does not affect productivity. Homozygotes die at birth due to a lack of contraction of the diaphragm muscle.
When using the Ryr1AG mouse strain in a publication, please cite the originating article(s) and include JAX stock #028405 in your Materials and Methods section.