Overview

This gene trap mutation abolishes endogenous Lrsam1 gene function while expressing a B-geo reporter fusion protein from the disrupted locus. Mutant mice may be useful as a lacZ reporter for Lrsam1 expression or as a knockout model for studying the endosome-lysosome sorting pathway, and peripheral neuropathies, in particular Charcot-Marie-Tooth disease.

Donating Investigator

Robert Burgess, The Jackson Laboratory

Genetic overview

Genetic Background	Generation

Lrsam1^{Gt(RRK461)Byg}

Allele Type	Gene Symbol	Gene Name
Gene trapped (Reporter, Null/Knockout)	Lrsam1	leucine rich repeat and sterile alpha motif containing 1

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Research Applications

Research Tools
Neurobiology Research

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Details

Detailed Description

Lrsam1 or RIFLE (leucine rich repeat and sterile alpha motif containing 1) encodes an E3 ubiquitin ligase involved in the endosome to lysosome sorting pathway. It is associated with the axonal neuropathy, Charcot-Marie-Tooth disease type 2 (CMT2). Lrsam1 is expressed in the motor neurons of the ventral horn, cell bodies of peripheral sensory neurons in the dorsal root ganglia (DRG) and to a lessor extent in the brain stem.
Homozygous mice are viable, fertile and exhibit mild neuromuscular junction and axonal defects with the number of axons slightly reduced in the sensory and motor branches of the femoral nerve. In response to challenge with the neurotoxic agent acrylamide, mice show increased sensitivity and more rapid motor axon degeneration.
Mice heterozygous for the mutation exhibit a wider stance and turn their paws outward, however, gait is unimpaired.

This strain may be useful for studying peripheral neuropathies, in particular Charcot-Marie-Tooth disease.

Development

Bay Genomics gene trap embryonic stem (ES) cell line RRK461, derived from 129P2/OlaHsd and expressing B-geo (a fusion of B-galactosidase and neomycin phospotransferase II), was sequenced to locate the Lrsam1 gene trap insertion site at position 1149 of intron 22. ES cells were cultured and microinjected into blastocysts. Resultant chimeras were backcrossed to C57BL/6J for at least 5 generations by the donating laboratory. Western blot analysis demonstrates an absence of protein in mutants.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Bogdanik LP; Sleigh JN; Tian C; Samuels ME; Bedard K; Seburn KL; Burgess RW. 2013. Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease. Dis Model Mech 6(3):780-92PubMed: 23519028 MGI: J:196447

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Genetics

Lrsam1^{Gt(RRK461)Byg}

Allele Symbol: Lrsam1^{Gt(RRK461)Byg}

Allele Name	gene trap RRK461, BayGenomics
Allele Type	Gene trapped (Reporter, Null/Knockout)
Allele Synonym(s)
Gene Symbol and Name	Lrsam1, leucine rich repeat and sterile alpha motif containing 1
Gene Synonym(s)
Site of Expression	LacZ is expressed in place of the abolished endogenous Lrsam1 gene function in the motor neurons of the ventral horn, cell bodies of peripheral sensory neurons in the dorsal root ganglia and to a lessor extent in the brain stem.
Strain of Origin	129P2/OlaHsd
Chromosome	2
Molecular Note	The gene trap vector, RRK461, inserted at position 1149 of intron 22. Western blot analysis confirms the absence of protein expression.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Charcot-Marie-Tooth disease axonal type 2P

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Research Tools
- lacZ Expression
Neurobiology Research
- lacZ expression in neural tissue
- Charcot-Marie-Tooth Disease
- Neurodegeneration

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Lrsam1^{Gt(RRK461)Byg}/Lrsam1^{Gt(RRK461)Byg}
involves: 129P2/OlaHsd

nervous system phenotype

abnormal axon morphology
- number of axons in the motor branch of the femoral nerve is slightly reduced at >12 months of age compared to controls, although cross-sectional area of axons is unchanged
- average axon diameter in the sensory branch of the femoral nerve is slightly increased at >12 months of age compared to controls
- 5 month old mice treated with the neurotoxic agent acrylamide have reduced axon cross-sectional areas in the motor branch of the femoral nerve, suggesting a loss of large diameter axons

axon degeneration
- peripheral motor axons exhibit increased sensitivity to acrylamide-induced degeneration
- untreated mice exhibit modest differences in neuromuscular junction area and axon number

decreased nerve conduction velocity
- decrease in nerve conduction velocity is observed in 5 month old mice treated with the neurotoxic agent acrylamide for two weeks

abnormal neuromuscular synapse morphology
- area of neuromuscular junction of the tibialis anterior muscle is increased at 5 months of age, but is similar to control at > 12 months of age

Genotype: Lrsam1^{Gt(RRK461)Byg}/Lrsam1⁺
involves: 129P2/OlaHsd

behavior/neurological phenotype

abnormal limb posture
- paws turn outward
- wider stance than control, however gait, stride time, stance time and swing time are similar to control

nervous system phenotype

abnormal neuromuscular synapse morphology
- area of neuromuscular junction in the bone region of the tibialis anterior muscle is increased at 5 months of age, but is similar to control at > 12 months of age

abnormal axon morphology
- average axon diameter in the sensory branch of the femoral nerve is slightly decreased at >12 months of age compared to controls
- number of axons in the motor branch of the femoral nerve is slightly reduced at >12 months of age compared to controls, although cross-sectional area of axons is unchanged
- number of motor axons in the femoral nerve are reduced in 5 month old mice treated with the neurotoxic agent acrylamide

References

Bogdanik LP; Sleigh JN; Tian C; Samuels ME; Bedard K; Seburn KL; Burgess RW. 2013. Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease. Dis Model Mech 6(3):780-92PubMed: 23519028 MGI: J:196447

Additional - Lrsam1^{Gt(RRK461)Byg} related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Lrsam1
- Genotyping resources and troubleshooting
Breeding Considerations

While maintaining a live colony, these mice are bred as homozygotes.
- Additional Breeding and Husbandry Support
Citation
When using the B6.129P2-Lrsam1^{Gt(RRK461)Byg}/RwbMmjax mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #36934 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

See MMRRC for Additional Conditions of Distribution

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Lrsam1Gt(RRK461)Byg

Allele Symbol: Lrsam1Gt(RRK461)Byg

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Lrsam1Gt(RRK461)Byg/Lrsam1Gt(RRK461)Byginvolves: 129P2/OlaHsd

nervous system phenotype

Genotype: Lrsam1Gt(RRK461)Byg/Lrsam1+involves: 129P2/OlaHsd

behavior/neurological phenotype

nervous system phenotype

References

Additional - Lrsam1Gt(RRK461)Byg related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Lrsam1^{Gt(RRK461)Byg}

Allele Symbol: Lrsam1^{Gt(RRK461)Byg}

Genotype: Lrsam1^{Gt(RRK461)Byg}/Lrsam1^{Gt(RRK461)Byg}
involves: 129P2/OlaHsd

Genotype: Lrsam1^{Gt(RRK461)Byg}/Lrsam1⁺
involves: 129P2/OlaHsd

Additional - Lrsam1^{Gt(RRK461)Byg} related