Mice heterozygous for this ENU-induced (Lpin120884Nrcam20884) mutation possess a missense mutation in the phosphatidate phosphatase gene Lpin1 and a nonsense mutation in the neural cell adhesion molecule gene Nrcam. These mutant mice may be useful in studying neurodegeneration, myelin defects, muscle atrophy, and paralysis.
Brian Popko, University of Chicago
Mice heterozygous for this ENU-induced mutation (Lpin120884Nrcam20884), are viable and fertile, although the donating investigator reports that homozygous males do not breed and homozygous females fail to care of their pups. These double mutant mice possess a missense mutation in the phosphatidate phosphatase gene, Lpin1, and a nonsense mutation in the neural cell adhesion molecule gene, Nrcam. The two single mutations appear to act synergistically to produce the 20884 phenotype. The ENU20884 mutants exhibit demyelination and aberrant myelin structures, as well as severe electrophysiological abnormalities seen by a reduction in sciatic nerve conduction velocity and compound muscle action potentials. These mice develop a floppy gait leading to hindlimb paralysis, inability of the hindpaws to grip, visibly wasted hindquarter muscles, and the clenching of the hindlimbs to the body when suspended by the tail by 6 or 7 weeks of age. By 1 year of age, these mutants regain the ability to both grip structures and walk, although their gait remains floppy. These mutant mice may be useful in studying neurodegeneration, myelin defects, muscle atrophy, and paralysis.
Following multidose N-ethyl-N-nitrosourea (ENU) treatments to induce mutations in founder C57BL/6J mice, a forward genetic screen was utilized to identify a family of mice, ENU20884, exhibiting adult-onset hindlimb paralysis. Using a candidate gene approach two mutations were identified: the phosphatidate phosphatase gene, Lipin1 (Lpin1), and the neural cell adhesion molecule, neuron-glia-CAM-related cell adhesion molecule (Nrcam) gene. Sequencing of these genes identified a T to A transversion in exon 20 of Lpin1 resulting in a tyrosine to asparagine missense mutation (Y873N), and a C to T transition in exon 36 of Nrcam resulting in a premature stop codon (Q1033X). These mice, heterozygous for both mutations (Lpin120884Nrcam20884), were bred to littermates or to C57BL/6J mice to maintain a colony prior to arrival at The Jackson Laboratory. Upon arrival, mice were bred to C57BL/6J for at least one generation to establish the colony.
|Allele Type||Chemically induced (ENU)|
|Gene Symbol and Name||Lpin1, lipin 1|
|Strain of Origin||C57BL/6J|
|Molecular Note||A T to A transversion is located in exon 20 resulting in a tyrosine to asparagine missense mutation (Y873N). Western blot analysis showed similar levels of protein expression in all tissues examined except adipose tissue where protein levels are about twice that of controls. In adipose tissue from homozygous mutant mice phosphatidate phosphatase type 1 activity is reduced to about 20% of controls.|
|Allele Type||Chemically induced (ENU)|
|Gene Symbol and Name||Nrcam, neuronal cell adhesion molecule|
|Strain of Origin||C57BL/6J|
|Molecular Note||A C to T transition is located in exon 36 resulting in a premature stop codon (Q1033X). Semiquantitative PCR analysis indicates a decrease in mRNA levels. Western blot and immunohistochemical analysis failed to detect protein in homozygotes.|
When maintaining a live colony heterozygous double mutant mice may be bred to wildtype mice from the colony or to C57BL/6J. The donating investigator reports that homozygous males do not breed and homozygous females do not care for their young.
When using the C57BL/6J-Lpin120884 Nrcam20884/Mmjax mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #32029 in your Materials and Methods section.
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