Overview

The pale tremor (plt) allele is a spontaneous retrotransposon insertion in the Fig4 gene and is associated with Charcot-Marie-Tooth disease type 4J (CMT4J). Homozygous mice exhibit neuronal degeneration, juvenile lethality and diluted pigmentation.

Donating Investigator

Miriam Meisler, University of Michigan

Genetic overview

Genetic Background	Generation
	?+pN2F7 (2019-03-01 00:00:00)

Fig4^plt1

Allele Type	Gene Symbol	Gene Name
Spontaneous	Fig4	FIG4 phosphoinositide 5-phosphatase

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Research Applications

Neurobiology Research
Mouse/Human Gene Homologs

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Base Price

Starting at:

$328.00 Domestic price for female 4-week

356.51 Domestic price for breeder pair

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Details

Detailed Description

The pale tremor (plt) allele is a spontaneous retrotransposon insertion in the Fig4 gene. FIG4, a lipid phosphatase homolog of the yeast SAC (suppressor of actin), catalyzes removal of a phosphate from PI(3.5)P2, a membrane-bound phospholipid involved in the trafficking and fusion of intracellular vesicles. Mutations in human FIG4 are associated with Charcot-Marie-Tooth disease type 4J (CMT4J). Initially identified by tremors, an abnormal gait, which progresses to a loss of mobility, small size, juvenile lethality and diluted pigmentation, homozygous mice are characterized by spongiform degeneration of the brain and loss of neurons from peripheral ganglia. Neuron loss and accumulation of cytoplasmic vacuoles is observed in layers 4 and 5 of the cortex, deep cerebellar nuclei, and dorsal root ganglia. Homozygote survival is dependent on strain background. On the C57BL/6 background, homozygotes are neonatal lethal; on a C3H background homozygotes survive to two weeks; on a mixed C57BL/6 and C3HeB/FeJ background, homozygotes survive 4-6 weeks. These mice may be useful in studies of Charcot-Marie-Tooth disease type 4J.

Development

The pale tremor plt mutation arose spontaneously on a mixed strain background that included C57BL/6J, C3H, 129P2/Ola and SJL in the laboratory of Dr. Miriam Meisler at the University of Michigan. Mice carrying the mutation have been crossed for at least 21 generations to C57BL/6J. Pale tremor is a 5.5 kB ETn2b retrotransposon insertion in the FIG4 homolog Fig4 gene. The retrotransposon is inserted 384 bp upstream of exon 19 and results in abnormal splicing from exon 18. Low levels of transcript cannot be detected by Northern blot, but can be detected by RT-PCR. Functionally, plt is a null mutation. The strain is maintained as a cross to C57BL/6. Upon arrival, transgenic mice were bred to C57BL/6J inbred mice (Stock No. 000664) 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

Chow CY; Zhang Y; Dowling JJ; Jin N; Adamska M; Shiga K; Szigeti K; Shy ME; Li J; Zhang X; Lupski JR; Weisman LS; Meisler MH. 2007. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 448(7149):68-72PubMed: 17572665 MGI: J:122737

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Genetics

Fig4^plt1

Allele Symbol: Fig4^plt1

Allele Name	pale tremor
Allele Type	Spontaneous
Allele Synonym(s)	Fig4^-; Fig4^paletremor; plt
Gene Symbol and Name	Fig4, FIG4 phosphoinositide 5-phosphatase
Gene Synonym(s)
Strain of Origin	mixed
Chromosome	10
Molecular Note	The mouse retrotransposon ETn2Beta was inserted 384 bp upstream of exon 19 in the same orientation as the gene and was flanked by a duplication of the hexanucleotide CCCCTG. Northern blot did not detect transcript from mutants using a cDNA probe containing exons 8-15.
Mutations Made By	Miriam Meisler, University of Michigan

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).

Research Areas By Phenotype

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

Neurobiology Research
- Charcot-Marie-Tooth Disease
- Ataxia (Movement) Defects
- Neurodegeneration
Mouse/Human Gene Homologs
- Charcot-Marie-Tooth disease

Mammalian Phenotype Terms by Genotype

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

Genotype: Fig4^plt1/Fig4^plt1
involves: 129 * C3H * C57BL/6J * CAST/Ei * SJL

integument phenotype

diluted coat color

pigmentation phenotype

hypopigmentation

diluted coat color

mortality/aging

premature death
- survive to 1 -2 months of age

nervous system phenotype

astrocytosis

abnormal myelin sheath morphology
- thinning of the myelin sheath of the sciatic nerve

decreased nerve conduction velocity
- in the sciatic nerve

neuron degeneration
- neurons in layers 4 and 5 of the cortex, the deep cerebellar nuclei, and the dorsal root ganglia are severely affected with accumulation of vacuoles that fill the cytoplasm
- extensive loss of neurons from peripheral ganglia

neurodegeneration
- severe spongiform degeneration in the brain and extensive loss of neurons from the peripheral ganglia

abnormal brain morphology
- extensive autophagic inclusion bodies

abnormal sciatic nerve morphology
- thinning of the myelin sheath of the sciatic nerve

spongiform encephalopathy

Genotype: Fig4^plt1/Fig4^plt1
involves: 129P2/OlaHsd * C3H * C57BL/6 * CAST/Ei * SJL

immune system phenotype

spleen hypoplasia
- severe tremors develop 2 weeks after birth

integument phenotype

decreased hair follicle number
- pigment containing hair follicles are decreased in number

diluted coat color
- at P3

abnormal hair follicle morphology
- clumps of melanosomes are visible in the few remaining pigmented hair follicles

mortality/aging

premature death
- all mice die by 6 weeks
- juvenile lethality at 6-8 weeks of age

muscle phenotype

muscle weakness

nervous system phenotype

abnormal action potential
- sciatic nerves have reduced amplitude of compound muscle action potential

neuron degeneration
- visible at week 1, mice exhibit neonatal degeneration in sensory and autonomic ganglia with loss of neurons in from layers 4 and 5 of the cortex, deep cerebellar nuclei, thalamus, pons and medulla

abnormal motor neuron morphology
- at 6 weeks, spinal motor neurons accumulates vacuoles prior to cell loss

abnormal sciatic nerve morphology
- sciatic nerve conduction velocity is slowed
- sciatic nerves have reduced amplitude of compound muscle action potential
- mice exhibit fewer large-diameter myelinated axons

abnormal nerve conduction
- sciatic nerve conduction velocity is slowed
- sciatic nerve conduction velocity reduced to 50% of velocity in control mice

demyelination
- low abundance of myelin basic protein
- reduced sciatic nerve myelination

abnormal nervous system morphology

spongiform encephalopathy
- in deep layers of cortex, cerebellar nuclei, hippocampus, brainstem, and dorsal root ganglia

astrocytosis

behavior/neurological phenotype

abnormal motor capabilities/coordination/movement
- severe movement disorder by 30 days of age

abnormal gait
- mice have a 'swimming' gait

tremors
- by 30 days of age

abnormal limb posture
- at week 3

impaired coordination
- progressive loss of mobility

pigmentation phenotype

diluted coat color
- at P3

abnormal melanosome morphology
- clumps of melanosomes are visible in the few remaining pigmented hair follicles

growth/size/body region phenotype

decreased body size
- at P3

decreased body weight

hematopoietic system phenotype

spleen hypoplasia
- severe tremors develop 2 weeks after birth

Genotype: Fig4^plt1/Fig4^plt1
involves: 129P2/OlaHsd * C3H * SJL

craniofacial phenotype

abnormal craniofacial morphology
- craniofacial morphology is altered

long incisors
- relative overgrowth of incisors

skeleton phenotype

abnormal osteoblast morphology
- extensive vacuolization is seen in cultures of isolated osteoblasts from calvarial tissue

small clavicle
- Normal - however, pelvic bone shape is normal in newborns and at P21
- clavicles are 20-25% smaller at P21 than in wild-type, however their shape is normal

abnormal bone ossification

abnormal skeleton morphology
- skeleton is normal at birth but is smaller at P21

decreased trabecular bone connectivity density

abnormal trabecular bone morphology
- lower trabecular density of bones and reduction in size and density of trabeculae in vertebrae
- trabecular separation is increased more than 3-fold

decreased bone trabecula number

decreased compact bone thickness
- femoral cortical thickness is reduced to less than 50% of wild-type values

decreased bone volume

decreased trabecular bone volume

abnormal bone structure
- bone volume fraction, bone surface, trabecular number and connectivity density are reduced to less than 50% of wild-type values

abnormal compact bone morphology
- lower cortical density of bones

long incisors
- relative overgrowth of incisors

decreased length of long bones
- long bones are 20-25% smaller at P21 than in wild-type

growth/size/body region phenotype

decreased body weight

postnatal growth retardation
- impaired growth; skeleton is normal at birth but is smaller at P21

long incisors
- relative overgrowth of incisors

hematopoietic system phenotype

abnormal bone marrow cell morphology/development
- extensive vacuolization is seen in cultures of bone marrow mesenchymal stroma

mammalian phenotype

limbs/digits/tail phenotype
- Normal - mice do not exhibit aplasia or hypoplasia of digits on the front or rear limb

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

Genotype: Fig4^plt1/Fig4^plt1
B6.Cg-Fig4

cardiovascular system phenotype

abnormal heart atrium morphology
- significant degeneration of the atria with large, transparent vacuoles

References

Chow CY; Zhang Y; Dowling JJ; Jin N; Adamska M; Shiga K; Szigeti K; Shy ME; Li J; Zhang X; Lupski JR; Weisman LS; Meisler MH. 2007. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 448(7149):68-72PubMed: 17572665 MGI: J:122737

Additional - Fig4^plt1 related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Fig4 Alternate1
- Genotyping resources and troubleshooting
Breeding Considerations

While maintaining a live colony, these mice are bred as heterozygotes. Homozygote survival is dependent on strain background. On the C57BL/6 background, homozygotes are neonatal lethal; on a C3H background homozygotes survive to two weeks; on a mixed background, homozygotes survive 4-6 weeks.
- Additional Breeding and Husbandry Support
Citation
When using the B6.Cg-Fig4^plt1/MmJ mouse strain in a publication, please cite the originating article(s) and include JAX stock #017800 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

AX18 (Maximum)

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Available

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Commercial & For-Profit

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International Pricing for

Commercial & For-Profit

Not-For-Profit & Academic

Live Mouse

Age

Genotype

Price

weeks

Breeder Pair

Sex

Genotype

Price

Female
Male

Cryorecovery - Pricing

Service/Product	Description	Price
> >	Heterozygous or wildtype for Fig4<plt1>

Related Products and Services

Frozen Mouse Embryo	B6.Cg-Fig4<plt1>/MmJ	$2595.00
Frozen Mouse Embryo	B6.Cg-Fig4<plt1>/MmJ	$2595.00
Frozen Mouse Embryo	B6.Cg-Fig4<plt1>/MmJ	$3373.50
Frozen Mouse Embryo	B6.Cg-Fig4<plt1>/MmJ	$3373.50

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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

Questions about Terms of Use

Additional Use Restrictions Apply

Use of MICE by companies or for-profit entities requires a no-fee JAX Leap License prior to shipping.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Fig4plt1

Allele Symbol: Fig4plt1

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:

Mammalian Phenotype Terms by Genotype

Genotype: Fig4plt1/Fig4plt1involves: 129 * C3H * C57BL/6J * CAST/Ei * SJL

integument phenotype

pigmentation phenotype

mortality/aging

nervous system phenotype

Genotype: Fig4plt1/Fig4plt1involves: 129P2/OlaHsd * C3H * C57BL/6 * CAST/Ei * SJL

immune system phenotype

integument phenotype

mortality/aging

muscle phenotype

nervous system phenotype

behavior/neurological phenotype

pigmentation phenotype

growth/size/body region phenotype

hematopoietic system phenotype

Genotype: Fig4plt1/Fig4plt1involves: 129P2/OlaHsd * C3H * SJL

craniofacial phenotype

skeleton phenotype

growth/size/body region phenotype

hematopoietic system phenotype

mammalian phenotype

Genotype: Fig4plt1/Fig4plt1B6.Cg-Fig4

cardiovascular system phenotype

References

Additional - Fig4plt1 related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Live Mouse

Breeder Pair

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

Fig4^plt1

Allele Symbol: Fig4^plt1

Genotype: Fig4^plt1/Fig4^plt1
involves: 129 * C3H * C57BL/6J * CAST/Ei * SJL

Genotype: Fig4^plt1/Fig4^plt1
involves: 129P2/OlaHsd * C3H * C57BL/6 * CAST/Ei * SJL

Genotype: Fig4^plt1/Fig4^plt1
involves: 129P2/OlaHsd * C3H * SJL

Genotype: Fig4^plt1/Fig4^plt1
B6.Cg-Fig4

Additional - Fig4^plt1 related