Overview

Also Known As:NMF380

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This F1061S point substitution in the SEA domain of Agrin provides a viable model for congenital myasthenic syndrome type 8 (CMS8), with homozygotes showing degradation of neuromuscular junctions at varying rates in specific muscles, a phenotype which progresses to premature death.

Genetic overview

Genetic Background	Generation
000664 C57BL/6J

Agrn^nmf380

Allele Type	Gene Symbol	Gene Name
Chemically induced (ENU)	Agrn	agrin

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Research Applications

Neurobiology Research

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Details

Detailed Description

Null alleles of agrin cause embryonic lethality with failed formation of neuromuscular junctions, but this F1061S point substitution in the SEA domain in the SN form of Agrin provides a viable model for congenital myasthenic syndrome type 8 (CMS8). Although no change was detected in transcript quantity or size and the alternative splicing at the Z splice site of exons 32 and 33 appears normal, this mutation is a partial loss of function hypomorph with decreased glycosylation of the mutant protein. Cell transfection studies show that this point mutation can decrease proteolysis of this protein by neurotrypsin and result in decreased externalization and secretion.

Agrn^nmf380 homozygotes are generally smaller than littermate controls by 15 days of age, there is muscle stiffness and atrophy, with their hind limbs appearing to be too weak to carry the weight, remaining low during movement, and they generally die between a few weeks to a few months of age. Initial pathology assessment on three mutants (27 - 34 days of age) revealed neurogenic myopathy with small and regenerating muscle fibers. Toes, especially those of hind paws may not fully extend, and hind limbs may move together rather than alternate. Brief spasms of hind or front limbs can also be observed. When lifting the mice by their tail, hind limbs remain clasped to the body. They develop an intense body tremor during movement and at rest due to postnatal degradation of neuromuscular junctions that proceeds at different rates in different muscles. The onset of the outward phenotype is approximately 2 weeks of age, although some muscles show perinatal neuromuscular degeneration. Defects of the neuromuscular junctions include smaller, underdeveloped postsynaptic sites, diminished alpha-bungarotoxin staining indicating decreased acetylcholine esterase receptors, and motor nerve terminals that sprout beyond the endplates. Transmission electron microscopy of the neuromuscular junctions from the plantaris muscle at 20 days of age showed abnormalities including extensive subsynaptic reticulum not continuous with the plasma membrane and decreased acetylcholine esterase and beta-dystroglycan from the neuromuscular junction. Genetic background impacts the phenotype of Agrn^nmf380, with the severity in homozygotes being similar when backcrossed to FVB/NJ, DBA/2J, or BALB/cJ, but much less severe when backcrossed to N3 on CAST/EiJ.

The degeneration of neuromuscular junctions in these mutants varies between different muscles. The diaphragm shows overgrowth of presynaptic endings and indistinct alpha-bungarotoxin staining by 1 day of age and almost no intact neuromuscular junctions by P14. The tibialis anterior appears normal in newborns, but by P14 disaggregating neuromuscular junctions are found. The neuromuscular junctions of the soleus appear normal at P4 but not by P14. The triangularis sterni show normal innervation at P9, but decreased alpha-bungarotoxin staining and abnormal presynaptic morphology by P13, and by P18 the neuromuscular junctions were found to be degraded both pre- and post-synaptically. However, the extraocular muscles do not show neuromuscular degeneration at P30. Assessment of the tibialis anterior and gastrocnemius muscles found that neuromuscular disaggregation and denervation occurs in the medial before the intermediate region. It is worthy of note that retraction or degeneration of the axons of peripheral nerves was not found. (Bogdanik and Burgess, 2011.)

Development

This phenotypic deviant was generated by ethylnitrosourea (ENU) mutagenesis in C57BL/6J males (Stock No. 000664), in the Neuroscience Mutagenesis facility at The Jackson Laboratory. Mutagenized males were crossed to C57BL/6J females; G3 descendants of the mutagenized males were selected for neurological impairment.

Control Suggestions

+/? untyped from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Bogdanik LP; Burgess RW. 2011. A valid mouse model of AGRIN-associated congenital myasthenic syndrome. Hum Mol Genet 20(23):4617-33PubMed: 21890498 MGI: J:176117

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Genetics

Agrn^nmf380

Allele Symbol: Agrn^nmf380

Allele Name	neuroscience mutagenesis facility, 380
Allele Type	Chemically induced (ENU)
Allele Synonym(s)	NMF380
Gene Symbol and Name	Agrn, agrin
Gene Synonym(s)
Strain of Origin	C57BL/6J
Chromosome	4
Molecular Note	This phenotypic mutation was identified in an ENU mutagenesis screen. The molecular mutation is an A to G conversion, resulting in the change of phenylalanine 1061 to serine (F1061S, numbered according to the SN form of the protein) in the SEA domain of the encoded protein.

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).

congenital myasthenic syndrome 8

Research Areas By Phenotype

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

Genotype: Agrn^nmf380 related

Neurobiology Research
- Neuroscience Mutagenesis Facility Strain

Mammalian Phenotype Terms by Genotype

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

Genotype: Agrn^nmf380/Agrn^nmf380
involves: BALB/c * C57BL/6J

mortality/aging

premature death
- mice exhibit the same reduction in lifespan as on a coisogenic C57BL/6J background

nervous system phenotype

abnormal neuromuscular synapse morphology
- mice exhibit the same degradation of neuromuscular junction (onset and progression) as on a coisogenic C57BL/6J background

Genotype: Agrn^nmf380/Agrn^nmf380
involves: C57BL/6J * DBA

mortality/aging

premature death
- mice exhibit the same reduction in lifespan as on a coisogenic C57BL/6J background

muscle phenotype

skeletal muscle atrophy
- Background Sensitivity - more severe on a C57BL/6J or DBA background than on other backgrounds

nervous system phenotype

abnormal neuromuscular synapse morphology
- mice exhibit the same degradation of neuromuscular junction (onset and progression) as on a coisogenic C57BL/6J background

Genotype: Agrn^nmf380/Agrn^nmf380
involves: C57BL/6J * FVB/N

mortality/aging

premature death
- mice exhibit the same reduction in lifespan as on a coisogenic C57BL/6J background

nervous system phenotype

abnormal neuromuscular synapse morphology
- mice exhibit the same degradation of neuromuscular junction (onset and progression) as on a coisogenic C57BL/6J background

Genotype: Agrn^nmf380/Agrn^nmf380
involves: C57BL/6J * CAST

mammalian phenotype

muscle phenotype
- Normal - unlike on other backgrounds, mice do not exhibit significant muscle atrophy

mortality/aging
- Normal - unlike on other backgrounds, mice survive for over a year

nervous system phenotype

abnormal neuromuscular synapse morphology
- Background Sensitivity - severity of neuromuscular junction degradation is reduced compared to in mice on a coisogenic C57BL/6J background
- neuromuscular junctions are abnormally shaped comapred to in wild-type mice

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

Genotype: Agrn^nmf380/Agrn^nmf380
C57BL/6J-Agrn/J

mammalian phenotype

nervous system phenotype
- Normal - mice exhibit normal axon numbers and size

mortality/aging

premature death
- mice die after a few weeks to a few months of age

muscle phenotype

muscle spasm
- homozygous mutants experience brief spasms of the front and/or hind limbs

myopathy
- cross sections of axial muscle from 3 mutant mice ages 27 - 34 days revealed neurogenic myopathy; atrophied, denervated muscle fibers and small, regenerating fibers exist among normal-appearing muscle fibers

abnormal skeletal muscle fiber type ratio
- at P20, mice exhibit increased type 1 slow msucle fibers in the gastrocnemius compared with wild-type mice

skeletal muscle atrophy
- Background Sensitivity - more severe on a C57BL/6J or DBA background than on other backgrounds

nervous system phenotype

abnormal neuromuscular synapse morphology
- diaphragm NMJs are abnormal at birth, severly affected at P4, and virtually completely degraded by P14 compared to in wild-type mice
- NMJ postnatal degradation varies in different muscles
- Normal - however, mice do not exhibit die-back neuropathy
- mice exhibit abnormal neuromuscular junctions (NMJs) morphology with smaller, simpler postsynaptic sites than in wild-type mice
- NMJ defects arise by P13 in the triangularis sterni with pre- and postsynaptic degradation at P18
- tibialis anterior NMJs are disaggregated by P14 compared to in wild-type mice

behavior/neurological phenotype

limb grasping
- when lifted by its tail, a mutant mouse keeps its hind limbs close to its body

paraparesis
- mutants' hind limbs appear weak, remaining low during locomotion

tremors
- homozygous mutant mice exhibit intense body tremor both during movement and when at rest

impaired limb coordination
- the hind limbs of homozygous mice often move together

abnormal motor capabilities/coordination/movement
- poor hindlimb motor control

growth/size/body region phenotype

decreased body size

limbs/digits/tail phenotype

abnormal hindlimb morphology
- hindlimb atrophy

camptodactyly
- homozygotes' toes, particularly those of the hind paws, may not extend fully

References

Bogdanik LP; Burgess RW. 2011. A valid mouse model of AGRIN-associated congenital myasthenic syndrome. Hum Mol Genet 20(23):4617-33PubMed: 21890498 MGI: J:176117

Additional - Agrn^nmf380 related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Sanger sequencing:Agrn
- Genotyping resources and troubleshooting
Breeding Considerations

These mutants are fragile and need special care to live beyond 6 weeks of age. Colony maintenance should use heterozygotes or ovarian transplantation and removal of unaffected littermates may improve the survival of the remaining mutant pups given increased maternal attention.
- Additional Breeding and Husbandry Support
Appearance
- black
  
  Related Genotype: a/a
Citation
When using the C57BL/6J-Agrn^nmf380/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #005469 in your Materials and Methods section.

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Also Known As:NMF380

Genetic overview

Research Applications

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Agrnnmf380

Allele Symbol: Agrnnmf380

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: Agrnnmf380 related

Mammalian Phenotype Terms by Genotype

Genotype: Agrnnmf380/Agrnnmf380involves: BALB/c * C57BL/6J

mortality/aging

nervous system phenotype

Genotype: Agrnnmf380/Agrnnmf380involves: C57BL/6J * DBA

mortality/aging

muscle phenotype

nervous system phenotype

Genotype: Agrnnmf380/Agrnnmf380involves: C57BL/6J * FVB/N

mortality/aging

nervous system phenotype

Genotype: Agrnnmf380/Agrnnmf380involves: C57BL/6J * CAST

mammalian phenotype

nervous system phenotype

Genotype: Agrnnmf380/Agrnnmf380C57BL/6J-Agrn/J

mammalian phenotype

mortality/aging

muscle phenotype

nervous system phenotype

behavior/neurological phenotype

growth/size/body region phenotype

limbs/digits/tail phenotype

References

Additional - Agrnnmf380 related

Genotyping Protocols

Breeding Considerations

Appearance

Citation

Strain Interest Registration

Contact Information

Interest

Terms Of Use

Licensing Information

Agrn^nmf380

Allele Symbol: Agrn^nmf380

Genotype: Agrn^nmf380 related

Genotype: Agrn^nmf380/Agrn^nmf380
involves: BALB/c * C57BL/6J

Genotype: Agrn^nmf380/Agrn^nmf380
involves: C57BL/6J * DBA

Genotype: Agrn^nmf380/Agrn^nmf380
involves: C57BL/6J * FVB/N

Genotype: Agrn^nmf380/Agrn^nmf380
involves: C57BL/6J * CAST

Genotype: Agrn^nmf380/Agrn^nmf380
C57BL/6J-Agrn/J

Additional - Agrn^nmf380 related