Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Spontaneous Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Generation +pN1 Generation Definitions   Donating Investigator Miriam Meisler,   University of Michigan

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 Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying   Fig4^plt1 allele

017801

C3Fe.Cg-Fig4plt1/MmJ

View Strains carrying   Fig4^plt1     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- 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).

Charcot-Marie-Tooth Disease, Type 4j; CMT4J

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Amyotrophic Lateral Sclerosis 11; ALS11   (FIG4)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Fig4^plt1/Fig4^plt1

        B6.Cg-Fig4^plt1

• cardiovascular system phenotype
• abnormal heart atrium morphology
  • significant degeneration of the atria with large, transparent vacuoles   (MGI Ref ID J:190368)

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Fig4^plt1/Fig4^plt1

        involves: 129P2/OlaHsd * C3H * C57BL/6 * CAST/Ei * SJL

• mortality/aging
• premature death
  • all mice die by 6 weeks   (MGI Ref ID J:122737)
  • juvenile lethality at 6-8 weeks of age   (MGI Ref ID J:185989)
• behavior/neurological phenotype
• abnormal motor capabilities/coordination/movement
  • severe movement disorder by 30 days of age   (MGI Ref ID J:185989)
• • abnormal gait
    • mice have a 'swimming' gait   (MGI Ref ID J:122737)
  • abnormal limb posture
    • at week 3   (MGI Ref ID J:122737)
  • impaired coordination
    • progressive loss of mobility   (MGI Ref ID J:122737)
  • tremors   (MGI Ref ID J:122737)
    • by 30 days of age   (MGI Ref ID J:185989)
• nervous system phenotype
• abnormal action potential
  • sciatic nerves have reduced amplitude of compound muscle action potential   (MGI Ref ID J:122737)
• abnormal nerve conduction
  • sciatic nerve conduction velocity is slowed   (MGI Ref ID J:122737)
  • sciatic nerve conduction velocity reduced to 50% of velocity in control mice   (MGI Ref ID J:185989)
• abnormal nervous system morphology   (MGI Ref ID J:185989)
• • abnormal motor neuron morphology
    • at 6 weeks, spinal motor neurons accumulates vacuoles prior to cell loss   (MGI Ref ID J:122737)
  • abnormal sciatic nerve morphology
    • mice exhibit fewer large-diameter myelinated axons   (MGI Ref ID J:122737)
    • sciatic nerve conduction velocity is slowed   (MGI Ref ID J:122737)
    • sciatic nerves have reduced amplitude of compound muscle action potential   (MGI Ref ID J:122737)
  • astrocytosis   (MGI Ref ID J:185989)
  • 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   (MGI Ref ID J:122737)
• demyelination
  • reduced sciatic nerve myelination   (MGI Ref ID J:185989)
  • low abundance of myelin basic protein   (MGI Ref ID J:185989)
• spongiform encephalopathy
  • in deep layers of cortex, cerebellar nuclei, hippocampus, brainstem, and dorsal root ganglia   (MGI Ref ID J:185989)
• muscle phenotype
• muscle weakness   (MGI Ref ID J:122737)
• growth/size phenotype
• decreased body size
  • at P3   (MGI Ref ID J:122737)
• • decreased body weight   (MGI Ref ID J:122737)
• hematopoietic system phenotype
• spleen hypoplasia
  • severe tremors develop 2 weeks after birth   (MGI Ref ID J:122737)
• immune system phenotype
• spleen hypoplasia
  • severe tremors develop 2 weeks after birth   (MGI Ref ID J:122737)
• pigmentation phenotype
• abnormal melanosome morphology
  • clumps of melanosomes are visible in the few remaining pigmented hair follicles   (MGI Ref ID J:122737)
• diluted coat color   (MGI Ref ID J:185989)
  • at P3   (MGI Ref ID J:122737)
• integument phenotype
• abnormal hair follicle morphology
  • clumps of melanosomes are visible in the few remaining pigmented hair follicles   (MGI Ref ID J:122737)
• • decreased hair follicle number
    • pigment containing hair follicles are decreased in number   (MGI Ref ID J:122737)
• diluted coat color   (MGI Ref ID J:185989)
  • at P3   (MGI Ref ID J:122737)

Fig4^plt1/Fig4^plt1

        involves: 129 * C3H * C57BL/6J * CAST/Ei * SJL

• mortality/aging
• premature death
  • survive to 1 -2 months of age   (MGI Ref ID J:173446)
• nervous system phenotype
• abnormal brain morphology
  • extensive autophagic inclusion bodies   (MGI Ref ID J:173446)
• abnormal myelin sheath morphology
  • thinning of the myelin sheath of the sciatic nerve   (MGI Ref ID J:173446)
• abnormal sciatic nerve morphology
  • thinning of the myelin sheath of the sciatic nerve   (MGI Ref ID J:173446)
• astrocytosis   (MGI Ref ID J:173446)
• decreased nerve conduction velocity
  • in the sciatic nerve   (MGI Ref ID J:173446)
• neurodegeneration
  • severe spongiform degeneration in the brain and extensive loss of neurons from the peripheral ganglia   (MGI Ref ID J:173446)
• • neuron degeneration
    • extensive loss of neurons from peripheral ganglia   (MGI Ref ID J:173446)
    • 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   (MGI Ref ID J:173446)
  • spongiform encephalopathy   (MGI Ref ID J:173446)
• pigmentation phenotype
• diluted coat color   (MGI Ref ID J:173446)
• hypopigmentation   (MGI Ref ID J:173446)
• integument phenotype
• diluted coat color   (MGI Ref ID J:173446)

View Research Applications

Research Applications

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

Mouse/Human Gene Homologs
Charcot-Marie-Tooth disease

Neurobiology Research
Ataxia (Movement) Defects
Neurodegeneration

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Fig4plt1
Allele Name		pale tremor
Allele Type		Spontaneous
Common Name(s)		Fig4paletremor; plt;
Mutation Made By		Miriam Meisler,   University of Michigan
Strain of Origin		mixed
Gene Symbol and Name		Fig4, FIG4 homolog (S. cerevisiae)
Chromosome		10
Gene Common Name(s)		A530089I17Rik; AI326867; ALS11; CMT4J; KIAA0274; RGD1311375; RIKEN cDNA A530089I17 gene; SAC3; dJ249I4.1; expressed sequence AI326867;
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. [MGI Ref ID J:122737]

Genotyping

Genotyping Information

Genotyping Protocols

Fig4^plt1, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

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):68-72. [PubMed: 17572665]  [MGI Ref ID J:122737]

Additional References

Fig4^plt1 related

Ferguson CJ; Lenk GM; Jones JM; Grant AE; Winters JJ; Dowling JJ; Giger RJ; Meisler MH. 2012. Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration. Hum Mol Genet 21(16):3525-34. [PubMed: 22581779]  [MGI Ref ID J:185989]

Ferguson CJ; Lenk GM; Meisler MH. 2009. Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum Mol Genet 18(24):4868-4878. [PubMed: 19793721]  [MGI Ref ID J:154296]

Katona I; Zhang X; Bai Y; Shy ME; Guo J; Yan Q; Hatfield J; Kupsky WJ; Li J. 2011. Distinct pathogenic processes between Fig4-deficient motor and sensory neurons. Eur J Neurosci 33(8):1401-10. [PubMed: 21410794]  [MGI Ref ID J:177325]

Lenk GM; Ferguson CJ; Chow CY; Jin N; Jones JM; Grant AE; Zolov SN; Winters JJ; Giger RJ; Dowling JJ; Weisman LS; Meisler MH. 2011. Pathogenic Mechanism of the FIG4 Mutation Responsible for Charcot-Marie-Tooth Disease CMT4J. PLoS Genet 7(6):e1002104. [PubMed: 21655088]  [MGI Ref ID J:173446]

Winters JJ; Ferguson CJ; Lenk GM; Giger-Mateeva VI; Shrager P; Meisler MH; Giger RJ. 2011. Congenital CNS Hypomyelination in the Fig4 Null Mouse Is Rescued by Neuronal Expression of the PI(3,5)P2 Phosphatase Fig4. J Neurosci 31(48):17736-51. [PubMed: 22131434]  [MGI Ref ID J:178138]

Zhang Y; McCartney AJ; Zolov SN; Ferguson CJ; Meisler MH; Sutton MA; Weisman LS. 2012. Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P(2) and PI(5)P. EMBO J 31(16):3442-56. [PubMed: 22842785]  [MGI Ref ID J:188700]

Zolov SN; Bridges D; Zhang Y; Lee WW; Riehle E; Verma R; Lenk GM; Converso-Baran K; Weide T; Albin RL; Saltiel AR; Meisler MH; Russell MW; Weisman LS. 2012. In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P. Proc Natl Acad Sci U S A 109(43):17472-7. [PubMed: 23047693]  [MGI Ref ID J:190368]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Breeding & Husbandry	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.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

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.

---

Ordering Information
JAX^® Mice
Surgical and Preconditioning Services
JAX^® Services
Customer Services and Support
Tel: 1-800-422-6423 or 1-207-288-5845
Fax: 1-207-288-6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries regarding Terms of Use

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice, Products & Services Conditions of Use

"MICE" means mouse strains, their progeny derived by inbreeding or crossbreeding, unmodified derivatives from mouse strains or their progeny supplied by The Jackson Laboratory ("JACKSON"). "PRODUCTS" means biological materials supplied by JACKSON, and their derivatives. "RECIPIENT" means each recipient of MICE, PRODUCTS, or services provided by JACKSON including each institution, its employees and other researchers under its control. MICE or PRODUCTS shall not be: (i) used for any purpose other than the internal research, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services. Acceptance of MICE or PRODUCTS from JACKSON shall be deemed as agreement by RECIPIENT to these conditions, and departure from these conditions requires JACKSON's prior written authorization.

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of mice, products or services, JACKSON will, at its option, provide credit or replacement for the mice or product received or the services provided.

No Liability

In no event shall JACKSON, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, PRODUCTS or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of JACKSON, its agents or employees. Unless prohibited by law, in purchasing or receiving MICE, PRODUCTS or services from JACKSON, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges JACKSON from all such causes of action or damages, and further agrees to defend and indemnify JACKSON from any costs or damages arising out of any third party claims.

MICE and PRODUCTS are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to JACKSON’s MICE, PRODUCTS or services. In addition, special terms and conditions of sale of certain MICE, PRODUCTS or services may be set forth separately in JACKSON web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, PRODUCTS and services by JACKSON, and by its licensees and distributors.

Acceptance of delivery of MICE, PRODUCTS or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on JACKSON, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, PRODUCTS or services by JACKSON.