Overview

Also Known As:neuromuscular degeneration 2 Jackson

Mice homozygous for the spontaneous neuromuscular degeneration (nmd-2J) mutation exhibit motor neuron degeneration leading to atropy of skeletal muscle fibers as early as postnatal week 2. Locomotor impairment progresses to paralysis, usually beginning in the hindlimbs. Most homozygous mutants die by 3.5-4 weeks of age. This strain is useful in studies of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).

Genetic overview

Genetic Background	Generation

Ighmbp2^nmd-2J

Allele Type	Gene Symbol	Gene Name
Spontaneous	Ighmbp2	immunoglobulin mu binding protein 2

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Research Applications

Neurobiology Research
Mouse/Human Gene Homologs

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$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Motor neuron diseases like amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are typified by the degeneration of alpha motor neurons in the spinal cord that subsequently leads to muscle atrophy. The nature of such neuromuscular disorders appears to be complex but spontaneous mouse mutants are helping to pinpoint critical genetic variables. The mouse neuromuscular degeneration nmd mutant mice express an autosomal recessive neurological disease where motor neurons degenerate causing the skeletal muscle fibers to atrophy. Behaviorally, these mice are easily identifiable by the second postnatal week. The hindlimbs are dorsally contracted and their locomotor activity is impaired, but balance is not adversely affected. They cannot extend their legs to stand erect or assume full posture on all four limbs. Homozygotes clench their hindlimbs when picked up by the tail and they are unable to grasp a cage cover when held against it. They can maintain proper balance, however, and do not circle, bob their heads, or fall over sideways. Paralysis usually begins in the hindlimbs and later develops in the forelimbs as the disease progresses. Most homozygous mutants die by 3.5-4 weeks of age. Heterozygotes are phenotypically and histologically normal.

The mutant phenotype is very similar to that seen in the human diseases ALS and SMA. The pathology displayed by the degenerating neurons in both species appears similar in that the affected cells seem to "fade away", or stain more lightly for hematoxylin and eosin (H&E) and luxol fast blue-cresylecht violet (LFB-CV). The "fading away" neurons are not swollen, rather the cytoplasmic and nuclear organelles, while normal in structure, appear less densely packed. The populations of motor neurons that are most highly affected by the mouse nmd alleles are those found in the lumbar region, whereas the neurons in the thoracic and cervical spinal cord regions appear primarily normal. Degenerating alpha motor neurons are also found in the sympathetic chain. The muscle fiber lesions contain a mixture of tiny muscle fibers and normally sized fibers. Compared to the proximal muscle groups, the distal musculature of the forelimbs and hindlimbs contain more severe atrophic lesions with adipose tissue abnormally appearing in some instances. The pathology appears limited to neuromuscular aspects since inflammatory and gliotic responses to the lesions are not detected. The overall pattern of muscle denervation and atrophy appears to be random. Finally, it is not clear why the motor neurons are selectively sensitive to the significantly reduced levels of IGHMBP2 given that this DNA binding protein is widely expressed across many cell types. DNA sequencing reveals the (nmd-2J) mutation has a single A to G transition in intron 4 which results in a cryptic splice donor (interfering with the normal transcript splicing) and produces an abnormally spliced transcript with an additional 23bp and a premature stop codon. RT-PCR analysis of various tissues, including brain and spinal cord, shows that the abnormal mutant splicing produces 20-25% wildtype splicing and 75-80% mutant splicing. (Cook et al., 1995; Cox et al., 1998; Schmalbruch et al., 1991; Grohmann et al., 2001; Mizuta et al., 1993; Chen et al., 1997; Zhang et al., 1999).

Development

The Ighmbp2^nmd-2J/Ighmbp2^nmd-2J mice arose spontaneously in the BKS.Cg-m +/+ Lepr^db (Stock No. 000642) strain at The Jackson Laboratory Mouse Mutant Resource in 1987. These were backcrossed 11 generations to C57BL/6J. At N12, embryos were frozen from male heterozygotes crossed to female C57BL/6J. DNA sequencing reveals the (nmd-2J) mutation has a single A to G transition in intron 4 which results in a cryptic splice donor (interfering with the normal transcript splicing) and produces an abnormally spliced transcript with an additional 23bp and a premature stop codon.

Control Suggestions

Untyped from the colony

Additional Information

Considerations for Choosing Controls

Genetics

Ighmbp2^nmd-2J

Allele Symbol: Ighmbp2^nmd-2J

Allele Name	neuromuscular degeneration 2 Jackson
Allele Type	Spontaneous
Allele Synonym(s)	nmd^2J
Gene Symbol and Name	Ighmbp2, immunoglobulin mu binding protein 2
Gene Synonym(s)
Strain of Origin	BKS.Cg-Dock7^m +/+ Lepr^db/J
Chromosome	19
Molecular Note	An A-to-G transition mutation in intron 4 results in the creation of a cryptic splice site and interferes with the normal splicing of the transcript. RT-PCR analysis on RNA derived from various tissues of homozygous mice demonstrated that approximately 20-25% of the transcripts were spliced normally, while 75-80% of the transcripts were spliced aberrantly. This allele also presents with a deletion of one of the two leucine codons at position 362 and 363 in exon 8 (SW:P40694).

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).

distal spinal muscular atrophy 1

Research Areas By Phenotype

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

Genotype: Ighmbp2^nmd-2J related

Neurobiology Research
- Spinal Muscular Atrophy (SMA)
- Amyotrophic Lateral Sclerosis (ALS)
- Neurodegeneration
Mouse/Human Gene Homologs
- Spinal Muscular Atrophy with Respiratory Distress Type I (SMARD1)

Neurobiology Research
- Amyotrophic Lateral Sclerosis (ALS)
- Spinal Muscular Atrophy (SMA)

Mammalian Phenotype Terms by Genotype

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

Genotype: Ighmbp2^nmd-2J/Ighmbp2^nmd-2J
BKS.Cg Dock7 +/+ Lepr-Ighmbp2

behavior/neurological phenotype

abnormal gait
- rely on forelimbs to crawl forward, but balance and righting responses are normal

abnormal grip strength
- unable to grasp cage cover when set upon it

hindlimb paralysis
- dorsally contracted hindlimbs cannot be extended to stand erect or assume full posture on four limbs

limb grasping
- clench hindlimbs when picked up by the tail

muscle phenotype

abnormal masseter muscle morphology
- atrophic muscle fibers in the masseter

abnormal skeletal muscle fiber morphology
- distal musculature of limbs more severely affected but focal areas of muscle degeneration proximally as well
- intermixture of very small muscle fibers with more normal fibers

abnormal temporalis muscle morphology
- atrophic muscle fibers in the temporalis muscle

nervous system phenotype

abnormal innervation pattern to muscle
- affected alpha motor neurons with pale staining nuclei and perikarya
- mostly in lumbar region

craniofacial phenotype

abnormal masseter muscle morphology
- atrophic muscle fibers in the masseter

abnormal temporalis muscle morphology
- atrophic muscle fibers in the temporalis muscle

growth/size/body region phenotype

abnormal masseter muscle morphology
- atrophic muscle fibers in the masseter

abnormal temporalis muscle morphology
- atrophic muscle fibers in the temporalis muscle

mortality/aging

premature death
- death usually by 3.5 weeks although survival for several months is possible if left with parents without normal siblings present

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

Genotype: Ighmbp2^nmd-2J/Ighmbp2^nmd-2J
B6.BKS-Ighmbp2/J

behavior/neurological phenotype

decreased grip strength
- age top
- much shorter latency to fall when suspended from a wire cage top much shorter latence to fall when suspended from a wire cage top much shorter latence to fall when suspended from a wire cage top much shorter latence to fall when suspended from a wire cage top

cellular phenotype

abnormal cell cytoskeleton morphology
- abnormal cytoskeletons in axons

myocardium necrosis

growth/size/body region phenotype

weight loss

homeostasis/metabolism phenotype

increased circulating creatine kinase level
- 3-7 days prior to clearly evident clinical signs of heart disease, total plasma CK and cardiac-specific CK-MB levels in 5- to 9-week-old mice become significantly elevated

pleural effusion

pulmonary edema
- consolidation of lungs

cardiovascular system phenotype

abnormal cardiovascular system physiology

abnormal heart morphology

abnormal heart valve morphology
- secondary valvular insufficiency

abnormal heart ventricle morphology

abnormal impulse conducting system conduction

abnormal intercalated disk morphology
- attenuated

abnormal myocardial fiber morphology
- few desmosomes

abnormal QRS complex
- prolonged and attenuated R waves

cardiac interstitial fibrosis

decreased heart rate

decreased systemic arterial systolic blood pressure
- decreased lower end systolic blood pressure

dilated cardiomyopathy
- as early as 4-6 weeks of age
- pale, flaccid, enlarged hearts with one or more thrombi

dilated heart atrium

dilated heart ventricle

increased heart rate variability

myocardial fiber degeneration
- degenerating and apoptotic
- nuclear blebbing

myocardium necrosis

prolonged P wave
- attenuated, sometimes split

prolonged PR interval
- prolonged P-R interval

thin ventricular wall

mortality/aging

premature death
- at 62 days for males and 76 days for females
- maximum life span is 138 days for females

muscle phenotype

abnormal diaphragm morphology
- development of diaphragmatic muscle degeneration occurs late, around 8-14 weeks

abnormal intercalated disk morphology
- attenuated

abnormal myocardial fiber morphology
- few desmosomes

centrally nucleated skeletal muscle fibers
- centralized nuclei in myocytes

dilated cardiomyopathy
- as early as 4-6 weeks of age
- pale, flaccid, enlarged hearts with one or more thrombi

increased variability of skeletal muscle fiber size
- variable fiber size

muscle degeneration
- severe diffuse myocyte degeneration and regeneration

myocardial fiber degeneration
- degenerating and apoptotic
- nuclear blebbing

myocardium necrosis

skeletal muscle fiber atrophy
- severe muscle wasting and hind limb contracture

skeletal muscle interstitial fibrosis
- and fatty infiltration

nervous system phenotype

abnormal axon morphology
- abnormal cytoskeletons
- process of myelination normal
- vacuolation occurs during the course of myelination or after myelination

abnormal innervation pattern to muscle
- axon numbers in quadriceps nerves significantly decrease with age from 3 weeks on, 40% reduction by 12-14 weeks

abnormal neuromuscular synapse morphology
- denervation of motor endplates increases dramatically as motor neuron degeneration progresses

abnormal Schwann cell morphology
- frequently show indications of secondary myelin degeneration
- sometimes lacking axons

motor neuron degeneration
- 40% loss of small caliber axons
- 56% of L4 motor axons lost
- most losses are of large axons
- numerous dystrophic axons in ventral roots
- significant neuronal loss by 7 weeks in all lumbar ventral roots examined

respiratory system phenotype

decreased pulmonary respiratory rate
- reduced breathing rate (bradypnea)

pleural effusion

pulmonary edema
- consolidation of lungs

References

Additional References

Cook SA; Johnson KR; Bronson RT; Davisson MT. 1995. Neuromuscular degeneration (nmd): a mutation on mouse chromosome 19 that causes motor neuron degeneration. Mamm Genome 6(3):187-91PubMed: 7749225 MGI: J:23584
Cox GA; Mahaffey CL; Frankel WN. 1998. Identification of the mouse neuromuscular degeneration gene and mapping of a second site suppressor allele. Neuron 21(6):1327-37PubMed: 9883726 MGI: J:51890
Grohmann K; Rossoll W; Kobsar I; Holtmann B; Jablonka S; Wessig C; Stoltenburg-Didinger G; Fischer U; Hubner C; Martini R; Sendtner M. 2004. Characterization of Ighmbp2 in motor neurons and implications for the pathomechanism in a mouse model of human spinal muscular atrophy with respiratory distress type 1 (SMARD1). Hum Mol Genet 13(18):2031-42PubMed: 15269181 MGI: J:92862
Grohmann K; Schuelke M; Diers A; Hoffmann K; Lucke B; Adams C; Bertini E; Leonhardt-Horti H; Muntoni F; Ouvrier R; Pfeufer A; Rossi R; Van Maldergem L; Wilmshurst JM; Wienker TF; Sendtner M; Rudnik-Schoneborn S; Zerres K; Hubner C. 2001. Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet 29(1):75-7PubMed: 11528396 MGI: J:71530
Mizuta TR; Fukita Y; Miyoshi T; Shimizu A; Honjo T. 1993. Isolation of cDNA encoding a binding protein specific to 5'-phosphorylated single-stranded DNA with G-rich sequences. Nucleic Acids Res 21(8):1761-6PubMed: 8493094 MGI: J:4973

Additional - Ighmbp2^nmd-2J related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Pyrosequencing:Ighmbp2PYRO
- Sanger sequencing:Ighmbp2 SEQ Alternate1
- Genotyping resources and troubleshooting
Breeding Considerations

Homozygotes die at about weaning age and must have a foster mother sent along with them.
- Additional Breeding and Husbandry Support
Appearance
- black, affected
  Related Genotype: a/a Ighmbp2^nmd-2J/Ighmbp2^nmd-2J
  
  black, unaffected
  Related Genotype: a/a Ighmbp2^nmd-2J/+ or a/a ?/+
Citation
When using the neuromuscular degeneration 2 Jackson mouse strain in a publication, please cite the originating article(s) and include JAX stock #002521 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

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or Wild-type for Ighmbp2<nmd-2J>

Related Products and Services

Frozen Mouse Embryo	B6.BKS-Ighmbp2<nmd-2J>/J Frozen Embryos	$2595.00
Frozen Mouse Embryo	B6.BKS-Ighmbp2<nmd-2J>/J Frozen Embryos	$2595.00
Frozen Mouse Embryo	B6.BKS-Ighmbp2<nmd-2J>/J Frozen Embryos	$3373.50
Frozen Mouse Embryo	B6.BKS-Ighmbp2<nmd-2J>/J Frozen Embryos	$3373.50

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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.

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Also Known As:neuromuscular degeneration 2 Jackson

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Ighmbp2nmd-2J

Allele Symbol: Ighmbp2nmd-2J

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:

Genotype: Ighmbp2nmd-2J related

Mammalian Phenotype Terms by Genotype

Genotype: Ighmbp2nmd-2J/Ighmbp2nmd-2JBKS.Cg Dock7 +/+ Lepr-Ighmbp2

behavior/neurological phenotype

muscle phenotype

nervous system phenotype

craniofacial phenotype

growth/size/body region phenotype

mortality/aging

Genotype: Ighmbp2nmd-2J/Ighmbp2nmd-2JB6.BKS-Ighmbp2/J

behavior/neurological phenotype

cellular phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

cardiovascular system phenotype

mortality/aging

muscle phenotype

nervous system phenotype

respiratory system phenotype

References

Additional References

Additional - Ighmbp2nmd-2J related

Genotyping Protocols

Breeding Considerations

Appearance

Citation

Animal Health Reports

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

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Ighmbp2^nmd-2J

Allele Symbol: Ighmbp2^nmd-2J

Genotype: Ighmbp2^nmd-2J related

Genotype: Ighmbp2^nmd-2J/Ighmbp2^nmd-2J
BKS.Cg Dock7 +/+ Lepr-Ighmbp2

Genotype: Ighmbp2^nmd-2J/Ighmbp2^nmd-2J
B6.BKS-Ighmbp2/J

Additional - Ighmbp2^nmd-2J related