Overview

Also Known As:fg, froggy

This strain is currently unavailable due to replenishing of cryopreserved stocks.

These Large^myd mice are a model of congenital muscular dystrophy type 1D (MDC1D; also called human α-dystroglycan glycosylation-deficient muscular dystrophy).

Genetic overview

Genetic Background	Generation

View Genetics

Research Applications

Neurobiology Research
Developmental Biology Research
Mouse/Human Gene Homologs

View All Research Applications

Details

Detailed Description

The spontaneous autosomal recessive mutation myodystrophy (myd) is a deletion in exons 5-7 of the glycotransferase gene (Large) on chromosome 8; causing a frameshift and premature stop codon before the first two catalytic domains. This Large^myd mutation results in abnormal glycosylation of its substrate α-dystroglycan.
Large^myd mice are a model of Congenital muscular dystrophy type 1D (MDC1D; also called human α-dystroglycan glycosylation-deficient muscular dystrophy). MYD/Le-Large^myd homozygotes exhibit a progressive myopathy, abnormal posture, thoracic kyphosis, calcium deposits in muscle, loss of Schwann cells and myelin, central nervous system defects, and reduced growth. Original characterization of these mice reported that myodystrophic (homozygous) mice were fertile but reproduction was very poor, and the mean lifespan of homozygotes that survived weaning was 17 weeks with a range of 5 to 39 weeks (Lane PW, Beamer TC, and Myers DD. J Hered. 1976. 67:135). As predicted by this, when breeding MYD/Le-Large^myd heterozygotes together at The Jackson Laboratory Repository, MYD/Le-Large^myd homozygous animals were small and died early.
Of note, Large^myd homozygotes on different genetic backgrounds are also described with sensorineural hearing loss (B6C3Fe) and eye defects (C57BL/6). Whether MYD/Le-Large^myd homozygotes manifest these defects is not specifically determined.

Development

The spontaneous autosomal recessive mutation myodystrophy (myd) is a deletion in exons 5-7 of the glycotransferase gene (Large) on chromosome 8; causing a frameshift and premature stop codon before the first two catalytic domains. The history of Stock No. 018305 is described below.

The myodystrophy mutation (Large^myd) was discovered at The Jackson Laboratory in 1963 on the lethal spotting stock LS/LeJ (Stock No. 000262; which had been imported from University College, London in 1961). The first myodystrophic male was outcrossed to a C57BL/6J female. Matings of a homozygous mouse with a heterozygous mouse were carried out as often as possible (or as heterozygous pairs). The Large^myd mutation was found on chromosome 8 in close linkage with the radiation-induced oligosyndactylism mutation (Os; heterozygotes are fertile with fused toes and homozygotes die in utero). As such, a Large^myd/+ male (generation F38) was bred to an ROP inbred female harboring the Os and pintail mutations (Stock No. 000267); this allowed for maintenance/tracking of the Large^myd mutation by Os phenotype). After three sibling matings, oligosyndactylic animals (heterozygous for the Os mutation; Os/+) were crossed seven times to the +/+ members of the strain. At N7, an Os/+ mouse was again crossed to a Large^myd/+ mouse to establish the Os and Large^myd mutations in repulsion. This repulsion strain (Stock No. 000300) was subsequently maintained by breeding oligosyndactylic siblings (Os +/+ Large^myd) together. Stock No. 000300 was cryopreserved in 1981 by mating Os +/+ Large^myd males at N7F22-F27 to non Os (+ +/+ ?) females.

In 2012, heterozygous Large^myd mice without fused toes (wildtype at the Os locus) were obtained and bred together as Stock No. 018305.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Genetics

Large1^myd

Allele Symbol: Large1^myd

Allele Name	myodystrophy
Allele Type	Spontaneous
Allele Synonym(s)	fg; froggy; Large^myd; myd
Gene Symbol and Name	Large1, LARGE xylosyl- and glucuronyltransferase 1
Gene Synonym(s)
Strain of Origin	STOCK Edn3^ls
Chromosome	8
Molecular Note	The mutation underlying the myodystrophy phenotype has been determined to be an intragenic deletion in the glycotransferase gene, Large. The deletion of exons 5-7 cause a frameshift and a premature stop codon before the first two catalytic domains.

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).

muscular dystrophy-dystroglycanopathy

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

facioscapulohumeral muscular dystrophy

Research Areas By Phenotype

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

Neurobiology Research
- Myelination Defects
  - peripheral neuropathy
- Muscular Dystrophy
  - Dystroglycanopathy
Developmental Biology Research
- Postnatal Lethality
  - Homozygous
Mouse/Human Gene Homologs
- Muscular Dystrophy, Congenital, Type 1D

Genotype: Large1^myd related

Neurobiology Research
- Muscular Dystrophy
  - Dystroglycanopathy

Mammalian Phenotype Terms by Genotype

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

Genotype: Large1^myd/Large1^myd
MYD/Le-Os +/+ Large/J

behavior/neurological phenotype

abnormal gait
- hind limbs held close to the body producing a short, shuffling gait
- hind limbs never extended and dragged

limb grasping
- adduction of hind legs, flexion of the knee, ankles and toes
- involves hind limbs
- severe contraction of hind limbs sometimes by 3-4 months of age

growth/size/body region phenotype

abnormal tongue morphology
- musculature of tongue not affected until later
- subepithelial fibrosis in tongues of older mice

decreased body weight
- organ weights reduced comparably with reduced body weigh

postnatal growth retardation
- growth improved after weaning but mice always small
- very severe at weaning

immune system phenotype

myositis
- mononuclear cell infiltration of areas surrounding degenerating fibers

mortality/aging

premature death
- average life span 17.25 weeks, range 5-39 weeks

muscle phenotype

abnormal muscle morphology

abnormal muscle physiology

abnormal skeletal muscle fiber morphology
- central migration of nuclei
- loss of striation
- nuclear "rowing"
- variable fiber size

calcified muscle
- elevated calcium levels in skeletal muscles, particularly the diaphragm
- heart not affected

dystrophic muscle

muscle degeneration

myopathy
- diffuse and progressive myopathy
- widely distributed focal lesions in skeletal muscles as early as 16 days of age

myositis
- mononuclear cell infiltration of areas surrounding degenerating fibers

nervous system phenotype

abnormal myelination
- areas where nerves are completely deficient in myelin

abnormal spinal nerve morphology
- areas completely deficient in myelin
- L3 and L4 ventral roots most severely affected
- not every root is affected
- observed in dorsal roots T13 to S1 and Ventral roots L1 to S1 (except L5)

absent Schwann cells
- usually unmyelinated nerves lack Schwann cells but sometimes Schwann cells present but lacking myelin

reproductive system phenotype

reduced fertility
- although not sterile, reproduction is very poor

skeleton phenotype

abnormal bone structure
- thinning of all bones examined

kyphosis
- becoming progressively worse with age
- thoracic kyphosis by 6-8 weeks of age

craniofacial phenotype

abnormal tongue morphology
- musculature of tongue not affected until later
- subepithelial fibrosis in tongues of older mice

digestive/alimentary phenotype

abnormal tongue morphology
- musculature of tongue not affected until later
- subepithelial fibrosis in tongues of older mice

Genotype: Large1^myd/Large1^myd
B6.Cg-Large1/Pjn

cardiovascular system phenotype

abnormal myocardium layer morphology
- lesions observed in the left and right atria and ventricles
- myocardium exhibits mild to moderate areas of cardiomyocyte degeneration with mycytolysis, necrosis and interstitial fibrosis in 5 month old mice

dilated cardiomyopathy
- adult onset

vision/eye phenotype

abnormal eye electrophysiology
- amplitude of b-wave responses is reduced and delayed at all flash intensities in 2 month old mice
- larger negative polarity a-wave in response to intermediate flash intensities in 2 month old mice
- maximum amplitude of a-wave reduced in response to highest flash intensities in 2 month old mice

abnormal retinal layer morphology

disorganized retinal outer plexiform layer
- exhibits extracelluelar edema
- layer is disorganized with a reduction in synaptic complexes
- layer is thinner than in control littermates
- mitochondria are swollen with severe disruption of cristae

thin retinal outer nuclear layer
- almost 50% thinner than in controls

muscle phenotype

abnormal diaphragm morphology
- by 4 months diaphragm exhibits necrosis and fatty infiltration
- exhibits prominent interstial fibrosis with extensive degeneration and regeneration of myofibers at 1.5 months of age

abnormal myocardium layer morphology
- lesions observed in the left and right atria and ventricles
- myocardium exhibits mild to moderate areas of cardiomyocyte degeneration with mycytolysis, necrosis and interstitial fibrosis in 5 month old mice

abnormal soleus morphology
- occasional signs of fiber-type grouping in 6 month old mice

dilated cardiomyopathy
- adult onset

Genotype: Large1^myd/Large1^myd
B6C3Fe a/a-Large1/J

behavior/neurological phenotype

abnormal gait
- variable severity at 3 weeks of age; some exhibit gait abnormalities and others could not be identified by this observation

limb grasping
- homozygous mice tightly adduct the hindlimbs and curl toes when suspended by the tail

homeostasis/metabolism phenotype

abnormal enzyme/coenzyme activity
- laminin-binding activity of alpha-dystroglycan is less than 5% of normal
- mice exhibit hypoglycosylation of almost all alpha-dystroglycan compared to in wild-type mice

increased circulating creatine kinase level
- affected animals have an elevated serum CK range compared to controls

immune system phenotype

myositis
- accompanies skeletal muscle fiber necrosis

muscle phenotype

abnormal myocardial fiber morphology
- mutants exhibit focal patches of cardiac myocyte membrane damage

abnormal myocardium layer morphology
- focal interstitial myocardial collagen deposition is seen at 10 months of age, indicating cardiac remodeling that occurs following myocardial damage

abnormal skeletal muscle fiber morphology

calcified muscle
- dystrophic calcification is seen ion areas of skeletal muscle necrosis

centrally nucleated skeletal muscle fibers

dystrophic muscle

increased variability of skeletal muscle fiber size
- both fast and slow muscle fiber types show increased size variation

myositis
- accompanies skeletal muscle fiber necrosis

skeletal muscle fiber degeneration
- foci of degeneration are typically large, irregularly shaped and involve 20-50 necrotic fibers
- many degenerating and regenerating fibers

skeletal muscle fiber necrosis
- in addition to foci of 20-50 necrotic fibers, individual or smaller groups of necrotic fibers are also seen

cardiovascular system phenotype

abnormal myocardial fiber morphology
- mutants exhibit focal patches of cardiac myocyte membrane damage

abnormal myocardium layer morphology
- focal interstitial myocardial collagen deposition is seen at 10 months of age, indicating cardiac remodeling that occurs following myocardial damage

cellular phenotype

skeletal muscle fiber necrosis
- in addition to foci of 20-50 necrotic fibers, individual or smaller groups of necrotic fibers are also seen

growth/size/body region phenotype

decreased body size
- variable severity at 3 weeks of age; some are clearly smaller and others could not be identified by size

hearing/vestibular/ear phenotype

abnormal auditory brainstem response waveform shape
- decreased wave IV amplitude
- mean wave IV threshold increased
- prolonged I-IV interpeak latencies

sensorineural hearing loss

Genotype: Large1^myd/Large1⁺
B6C3Fe a/a-Large1/J

behavior/neurological phenotype

limb grasping
- some aging animals exhibit atypical hindlimb posture and movements when lifted by the tail

References

Additional - Large1^myd related

Technical Support

CONTACT TECHNICAL SUPPORT

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

When maintaining a live colony, mice heterozygous for the Large^myd mutation are bred to wildtype mice from the colony. When breeding MYD/Le-Large^myd heterozygotes together at The Jackson Laboratory Repository, MYD/Le-Large^myd homozygous animals were small and died early.
- Additional Breeding and Husbandry Support
Citation
When using the MYD/Le Large1^myd/J mouse strain in a publication, please include JAX stock #018305 in your Materials and Methods section.

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Overview

Also Known As:fg, froggy

Genetic overview

Research Applications

Details

Detailed Description

Development

Control Suggestions

Additional Information

Genetics

Large1myd

Allele Symbol: Large1myd

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).

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Phenotype

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

Genotype: Large1myd related

Mammalian Phenotype Terms by Genotype

Genotype: Large1myd/Large1mydMYD/Le-Os +/+ Large/J

behavior/neurological phenotype

growth/size/body region phenotype

immune system phenotype

mortality/aging

muscle phenotype

nervous system phenotype

reproductive system phenotype

skeleton phenotype

craniofacial phenotype

digestive/alimentary phenotype

Genotype: Large1myd/Large1mydB6.Cg-Large1/Pjn

cardiovascular system phenotype

vision/eye phenotype

muscle phenotype

Genotype: Large1myd/Large1mydB6C3Fe a/a-Large1/J

behavior/neurological phenotype

homeostasis/metabolism phenotype

immune system phenotype

muscle phenotype

cardiovascular system phenotype

cellular phenotype

growth/size/body region phenotype

hearing/vestibular/ear phenotype

Genotype: Large1myd/Large1+B6C3Fe a/a-Large1/J

behavior/neurological phenotype

References

Additional - Large1myd related

Technical Support

Genotyping Protocols

Breeding Considerations

Citation

Strain Interest Registration

Contact Information

Interest

Terms Of Use

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

Related Strains

Large1^myd

Allele Symbol: Large1^myd

Genotype: Large1^myd related

Genotype: Large1^myd/Large1^myd
MYD/Le-Os +/+ Large/J

Genotype: Large1^myd/Large1^myd
B6.Cg-Large1/Pjn

Genotype: Large1^myd/Large1^myd
B6C3Fe a/a-Large1/J

Genotype: Large1^myd/Large1⁺
B6C3Fe a/a-Large1/J

Additional - Large1^myd related