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- Description
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Description
Strain Information
Former Names B6.BKS Ighmbp2nmd-2J/J (Changed: 14-NOV-05 ) B6.BKS-Ighmbp2nmd-2J/+ (Changed: 15-DEC-04 ) B6.Bks-m db x 8762J (Changed: 15-DEC-04 ) Type Congenic; Mutant Strain; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Appearance
black, affected
Related Genotype: a/a Ighmbp2nmd-2J/Ighmbp2nmd-2J
black, unaffected
Related Genotype: a/a Ighmbp2nmd-2J/+ or a/a ?/+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. (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 Ighmbp2nmd-2J/Ighmbp2nmd-2J mice arose spontaneously in the BKS.Cg-m +/+ Leprdb (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.
Control Information
| Control | ||
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| Untyped from the colony | ||
| Considerations for Choosing Controls | ||
Related Strains
Strains carrying Ighmbp2nmd-2J allele
View Strains carrying Ighmbp2nmd-2J (4 strains)
Additional Web Information
Congenic Nomenclature
Phenotype
Phenotype Information
Spinal Muscular Atrophy, Distal, Autosomal Recessive, 1; DSMA1 - Models with phenotypic similarity to human disease where etiologies involve orthologs.1
1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).
assigned by genotype
Ighmbp2nmd-2J/Ighmbp2nmd-2J
B6.BKS-Ighmbp2nmd-2J/J
- life span-post-weaning/aging
- premature death (MGI Ref ID J:90418)
- at 62 days for males and 76 days for females
- maximum life span is 138 days for females
- cardiovascular system phenotype
- abnormal cardiovascular system physiology (MGI Ref ID J:90418)
- abnormal impulse conducting system conduction (MGI Ref ID J:90418)
- abnormal PQ interval (MGI Ref ID J:90418)
- prolonged P-R interval
- abnormal QRS complex (MGI Ref ID J:90418)
- prolonged and attenuated R waves
- prolonged P wave (MGI Ref ID J:90418)
- and attenuated, sometimes split
- decreased heart rate (MGI Ref ID J:90418)
- decreased systolic blood pressure (MGI Ref ID J:90418)
- decreased lower end systolic blood pressure
- dilated cardiomyopathy (MGI Ref ID J:90418)
- as early as 4-6 weeks of age
- pale, flaccid, enlarged hearts with one or more thrombi
- creatine kinase and cardiac isoform elevaed by as much as 5 fold prior to clinical symptoms
- increased heart rate variability (MGI Ref ID J:90418)
- abnormal heart morphology (MGI Ref ID J:90418)
- abnormal cardiac valve morphology (MGI Ref ID J:90418)
- secondary valvular insufficiency
- abnormal heart ventricle morphology (MGI Ref ID J:90418)
- abnormal myocardial fiber morphology (MGI Ref ID J:90418)
- few desmosomes
- abnormal intercalated disc morphology (MGI Ref ID J:90418)
- attenuated
- myocardial fiber degeneration (MGI Ref ID J:90418)
- degenerating and apoptotic
- nuclear blebbing
- cardiac interstitial fibrosis (MGI Ref ID J:90418)
- dilated atria (MGI Ref ID J:90418)
- dilated cardiomyopathy (MGI Ref ID J:90418)
- as early as 4-6 weeks of age
- pale, flaccid, enlarged hearts with one or more thrombi
- creatine kinase and cardiac isoform elevaed by as much as 5 fold prior to clinical symptoms
- myocardial necrosis (MGI Ref ID J:90418)
- nervous system phenotype
- abnormal Schwann cell morphology (MGI Ref ID J:92862)
- frequently show indications of secondary myelin degeneration
- sometimes lacking axons
- abnormal axon morphology (MGI Ref ID J:92862)
- vacuolation occurs during the course of myelination or after myelination
- abnormal cytoskeletons
- process of myelination normal
- abnormal muscle innervation (MGI Ref ID J:92862)
- axon numbers in quadricps nerves significantly decrease with age from 3 weeks on, 40% reduction by12-14 weeks
- abnormal neuromuscular synapse morphology (MGI Ref ID J:92862)
- denervation of motor endplates increases dramatically as motor neuron degeneration progresses
- motor neuron degeneration (MGI Ref ID J:90418)
- significant neuronal loss by 7 weeks in all lumbar ventral roots examined
- 56% of L4 motor axons lost
- numerous dystrophic axons in ventral roots
- most losses are of large axons
- 40% loss of small caliber axons
- muscle phenotype
- abnormal diaphragm morphology (MGI Ref ID J:92862)
- development of diaphragmatic muscle degeneration occurs late, around 8-14 weeks
- abnormal myocardial fiber morphology (MGI Ref ID J:90418)
- few desmosomes
- abnormal intercalated disc morphology (MGI Ref ID J:90418)
- attenuated
- myocardial fiber degeneration (MGI Ref ID J:90418)
- degenerating and apoptotic
- nuclear blebbing
- dilated cardiomyopathy (MGI Ref ID J:90418)
- as early as 4-6 weeks of age
- pale, flaccid, enlarged hearts with one or more thrombi
- creatine kinase and cardiac isoform elevaed by as much as 5 fold prior to clinical symptoms
- muscle degeneration (MGI Ref ID J:90418)
- severe muscle wasting and hind limb contracture
- severe diffuse myocyte degeneration and regeneration
- centralized nuclei in myocytes
- variable fiber size
- myocardial necrosis (MGI Ref ID J:90418)
- skeletal muscle interstitial fibrosis (MGI Ref ID J:90418)
- and fatty infiltration
- behavior/neurological phenotype
- abnormal grip strength (MGI Ref ID J:90418)
- 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
- respiratory system phenotype
- decreased breathing frequency (MGI Ref ID J:90418)
- reduced breathing rate (bradypnea)
- pulmonary edema (MGI Ref ID J:90418)
- consolidation of lungs and pleural effusion
- growth/size phenotype
- weight loss (MGI Ref ID J:90418)
- homeostasis/metabolism phenotype
- pulmonary edema (MGI Ref ID J:90418)
- consolidation of lungs and pleural effusion
The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.
Ighmbp2nmd-2J/Ighmbp2nmd-2J
BKS.Cg m +/+ Leprdb-Ighmbp2nmd-2J
- life span-post-weaning/aging
- premature death (MGI Ref ID J:23584)
- death usually by 3.5 weeks although survival for several months is possible if left with parents without normal siblings present
- behavior/neurological phenotype
- abnormal gait (MGI Ref ID J:23584)
- rely on forelimbs to crawl forward, but balance and righting responses are normal
- abnormal grip strength (MGI Ref ID J:23584)
- unable to grasp cage cover when set upon it
- hindlimb paralysis (MGI Ref ID J:23584)
- dorsally contracted hindlimbs cannot be extended to stand erect or assume full posture on four limbs
- limb grasping (MGI Ref ID J:23584)
- clench hindlimbs when picked up by the tail
- muscle phenotype
- abnormal masseter muscle morphology (MGI Ref ID J:23584)
- atrophic muscle fibers in the masseter
- abnormal skeletal muscle fiber morphology (MGI Ref ID J:23584)
- intermixture of very small muscle fibers with more normal fibers
- distal musculature of limbs more severely affected but focal areas of muscle degeneration proximally as well
- abnormal temporalis muscle morphology (MGI Ref ID J:23584)
- atrophic muscle fibers in the temporalis muscle
- nervous system phenotype
- abnormal muscle innervation (MGI Ref ID J:23584)
- affected alpha motor neurons with pale staining nuclei and perikarya
- mostly in lumbar region
This mouse can be used to support research in many areas including:Ighmbp2nmd-2J related
Mouse/Human Gene Homologs
Spinal Muscular Atrophy with Respiratory Distress Type I (SMARD1)
Neurobiology Research
Neurodegeneration
Neuromuscular Defects
Genes & Alleles
Gene & Allele Information
| Allele Symbol | Ighmbp2nmd-2J | ||
|---|---|---|---|
| Allele Name | neuromuscular degeneration 2 Jackson | ||
| Allele Type | Spontaneous | ||
| Common Name(s) | nmd2J; | ||
| Strain of Origin | BKS.Cg-m +/+ Leprdb/J | ||
| Gene Symbol and Name | Ighmbp2, immunoglobulin mu binding protein 2 | ||
| Chromosome | 19 | ||
| Gene Common Name(s) | AEP; CATF1; FLJ34220; FLJ41171; HCSA; HMN6; MGC124598; RIPE3b1; SMARD1; SMUBP2; Smbp-2; Smbp2; immunoglobulin S mu binding protein 2; neuromuscular degeneration; nmd; p110 subunit; sma; spinal muscular atrophy; | ||
| 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. [MGI Ref ID J:51890] | ||
Genotyping
Genotyping Information
Genotyping Protocols
Ighmbp2nmd-2J, REST, vers. 1
Helpful Links
Optimizing PCR Protocols
References
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):187-91. [PubMed: 7749225] [MGI Ref ID 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):1327-37. [PubMed: 9883726] [MGI Ref ID 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):2031-42. [PubMed: 15269181] [MGI Ref ID 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):75-7. [PubMed: 11528396] [MGI Ref ID 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):1761-6. [PubMed: 8493094] [MGI Ref ID J:4973]
Ighmbp2nmd-2J relatedCook 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):187-91. [PubMed: 7749225] [MGI Ref ID 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):1327-37. [PubMed: 9883726] [MGI Ref ID 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):2031-42. [PubMed: 15269181] [MGI Ref ID J:92862]
Maddatu TP; Garvey SM; Schroeder DG; Hampton TG; Cox GA. 2004. Transgenic rescue of neurogenic atrophy in the nmd mouse reveals a role for Ighmbp2 in dilated cardiomyopathy. Hum Mol Genet 13(11):1105-15. [PubMed: 15069027] [MGI Ref ID J:90418]
Maddatu TP; Garvey SM; Schroeder DG; Zhang W; Kim SY; Nicholson AI; Davis CJ; Cox GA. 2005. Dilated cardiomyopathy in the nmd mouse: transgenic rescue and QTLs that improve cardiac function and survival. Hum Mol Genet 14(21):3179-89. [PubMed: 16174646] [MGI Ref ID J:102748]
Ruiz R; Lin J; Forgie A; Foletti D; Shelton D; Rosenthal A; Tabares L. 2005. Treatment with trkC agonist antibodies delays disease progression in neuromuscular degeneration (nmd) mice. Hum Mol Genet 14(13):1825-37. [PubMed: 15888478] [MGI Ref ID J:99795]
Health & husbandry
Health & Colony Maintenance Information
Colony Maintenance
Breeding & Husbandry Homozygotes die at about weaning age and must have a foster mother sent along with them.
Purchasing information
Pricing, Supply Level & Notes, Controls, General Terms & Conditions
Pricing
| Pricing for USA, Canada and Mexico shipping destinations |
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*Price(s) in US dollars ($)
Weeks of Age Price* Gender Cryorecovery Fee $1900.00
Additional Supply Details
| Supply Notes |
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| Pricing for International shipping destinations |
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*Price(s) in US dollars ($)
Weeks of Age Price* Gender Cryorecovery Fee $2470.00
Additional Supply Details
| Supply Notes |
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Supply Details
| Standard Supply | Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information. |
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| Supply Notes |
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Control Information
| Control | ||
|---|---|---|
| Untyped from the colony | ||
| Considerations for Choosing Controls | ||
| USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains. | ||
| International - Control Pricing Information for Genetically Engineered Mutant Strains. | ||
General Terms and Conditions
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