Overview

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.

Donating Investigator

Brian Popko, University of Chicago

Genetic overview

Genetic Background	Generation

Lpin1²⁰⁸⁸⁴

Allele Type	Gene Symbol	Gene Name
Chemically induced (ENU)	Lpin1	lipin 1

Nrcam²⁰⁸⁸⁴

Allele Type	Gene Symbol	Gene Name
Chemically induced (ENU)	Nrcam	neuronal cell adhesion molecule

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Research Applications

Neurobiology Research
Developmental Biology Research

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Details

Detailed Description

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.

Development

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.

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Douglas DS; Moran JL; Bermingham JR Jr; Chen XJ; Brindley DN; Soliven B; Beier DR; Popko B. 2009. Concurrent Lpin1 and Nrcam mouse mutations result in severe peripheral neuropathy with transitory hindlimb paralysis. J Neurosci 29(39):12089-100PubMed: 19793967 MGI: J:153042

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Genetics

Lpin1²⁰⁸⁸⁴

Allele Symbol: Lpin1²⁰⁸⁸⁴

Allele Name	20884
Allele Type	Chemically induced (ENU)
Allele Synonym(s)
Gene Symbol and Name	Lpin1, lipin 1
Gene Synonym(s)
Strain of Origin	C57BL/6J
Chromosome	12
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.

Nrcam²⁰⁸⁸⁴

Allele Symbol: Nrcam²⁰⁸⁸⁴

Allele Name	20884
Allele Type	Chemically induced (ENU)
Allele Synonym(s)
Gene Symbol and Name	Nrcam, neuronal cell adhesion molecule
Gene Synonym(s)
Strain of Origin	C57BL/6J
Chromosome	12
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.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Neurobiology Research
- Behavioral and Learning Defects
- Channel and Transporter Defects
  - sodium
- Neuromuscular defects
- Myelination Defects
  - peripheral neuropathy
- Neurodegeneration
Developmental Biology Research
- Neurodevelopmental Defects

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Lpin1²⁰⁸⁸⁴/Lpin1²⁰⁸⁸⁴ Nrcam²⁰⁸⁸⁴/Nrcam²⁰⁸⁸⁴
involves: C57BL/6J

growth/size/body region phenotype

decreased body weight
- associated with onset of paralysis and muscle wasting
- body weight recovers in association with attenuation of paralysis and muscle wasting

muscle phenotype

skeletal muscle fiber atrophy
- widespread atrophic fibers are seen in the hindquarters of mice with hindlimb paralysis

behavior/neurological phenotype

abnormal nursing
- appear to be incapable of suckling pups

decreased grip strength
- at 4 weeks of age hindlimb grip strength is significantly reduced
- at 6 weeks of age half of the mice are unable to grip with their hindpaws
- between 32 and 48 weeks of age all mice regain the ability to grip with their hindpaws
- reduced forelimb grip strength is seen at 6 weeks of age, weakness attenuates starting around 24 weeks of age
- by 8 weeks of age all of the mice are unable to grip with their hindpaws

hindlimb paralysis
- between 8 months and 1 year of age mice regain the ability to grip structures and walk although the gait remains floppy
- paralysis phenotype attenuates over time
- paralysis is characterized by partial to total loss of hindlimb joint mobility, inability to grip with the hind paws, and hindlimb grasping when suspended by the tail
- after 14 weeks of age hindlimbs take on a flaccid disposition and progressively regain mobility and strength
- develop hindlimb paralysis by 6 to 7 weeks of age

paresis
- paralysis is characterized by partial to total loss of hindlimb joint mobility, inability to grip with the hind paws, and hindlimb grasping when suspended by the tail
- develop hindlimb paralysis by 6 to 7 weeks of age

abnormal sexual interaction
- males do not breed

limb grasping
- hindlimb grasping

abnormal gait
- develop a floppy gait by 5 weeks of age

nervous system phenotype

demyelination
- at 8 and 12 weeks of age demyelinated axons are present in the sciatic nerve
- at 52 weeks of age some demyelinated axons are still present but the overall state of myelination has improved
- demyelination peaks at 8 weeks of age

abnormal sciatic nerve morphology
- at 8 weeks of age demyelinated axons are present and darkly stained debris is seen in the sciatic nerve
- appear less well organized compared to controls

abnormal action potential
- compound muscle action potentials are reduced at 8 and 12 weeks of age in the sciatic nerve and the sural nerve

abnormal myelin sheath morphology
- at 12 weeks of age some axons in the sciatic nerve have thin myelin sheaths
- at 12 weeks of age compact myelin structures are seen beside axons within Schwann cells
- at 52 weeks of age some axons with thin myelin sheaths are still present but the overall state of myelination has improved

decreased nerve conduction velocity
- at 4 and 8 weeks of age conduction velocity is reduced in the sciatic nerve and the sural nerve

skeleton phenotype

decreased joint mobility
- at the onset of paralysis joints appear stiff and are restricted to a bent position

References

Douglas DS; Moran JL; Bermingham JR Jr; Chen XJ; Brindley DN; Soliven B; Beier DR; Popko B. 2009. Concurrent Lpin1 and Nrcam mouse mutations result in severe peripheral neuropathy with transitory hindlimb paralysis. J Neurosci 29(39):12089-100PubMed: 19793967 MGI: J:153042

Additional - Lpin1²⁰⁸⁸⁴ related

Additional - Nrcam²⁰⁸⁸⁴ related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Pyrosequencing:Nrcam<20884>
- Pyrosequencing:Lpin1<20884>
- Genotyping resources and troubleshooting
Breeding Considerations

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.
- Additional Breeding and Husbandry Support
Mating System
- See "Breeding Considerations"
Citation
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.

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

Lpin120884

Allele Symbol: Lpin120884

Nrcam20884

Allele Symbol: Nrcam20884

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Lpin120884/Lpin120884 Nrcam20884/Nrcam20884involves: C57BL/6J

growth/size/body region phenotype

muscle phenotype

behavior/neurological phenotype

nervous system phenotype

skeleton phenotype

References

Additional - Lpin120884 related

Additional - Nrcam20884 related

Genotyping Protocols

Breeding Considerations

Mating System

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

Lpin1²⁰⁸⁸⁴

Allele Symbol: Lpin1²⁰⁸⁸⁴

Nrcam²⁰⁸⁸⁴

Allele Symbol: Nrcam²⁰⁸⁸⁴

Genotype: Lpin1²⁰⁸⁸⁴/Lpin1²⁰⁸⁸⁴ Nrcam²⁰⁸⁸⁴/Nrcam²⁰⁸⁸⁴
involves: C57BL/6J

Additional - Lpin1²⁰⁸⁸⁴ related

Additional - Nrcam²⁰⁸⁸⁴ related