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 Mutant Strain; Spontaneous Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse

Appearance
agouti, ataxic, tremors
Related Genotype: A/A Lpin1^fld-2J/Lpin1^fld-2J

agouti, unaffected
Related Genotype: A/A Lpin1^fld-2J/+

Description
Homozygous fatty liver dystrophy (fld) mice have an enlarged, fatty liver and hypertriglyceridemia which resolve to normal during the weaning transition. However, decreased overall size, decreased lipid in the fat pads, and a peripheral neuropathy persist throughout the lifespan. This peripheral neuropathy manifests as a tremor and an unsteady gait shortly after 10 days of age and worsens with age. The fld neuropathy is specific to the peripheral nervous system. Electron microscopy of sciatic nerves revealed thin, poorly compacted myelin sheaths, hypertrophic Schwann cells, myelin debris, degenerating axons, bands of Bugner, and regenerative clusters, but no evidence of inflammation (Langner et al, 1991). Western blot analysis of sciatic nerve from two-to-three month old fld/fld mice showed a 7-13-fold reduction in myelin P₀, a vast increase in apoE, an increase in GAP-43, and no detectable myelin P₂. It was also noted that an antibody to neurofilament 68K detected bands of lower molecular mass in the fld/fld sciatic nerve extracts than in wild-type, suggesting degradation of neurofilament 68K. Furthermore, TLC of fld/fld sciatic nerve lipids revealed decreased levels of phospholipids, glycosphingolipids, and some neutral lipids and increased levels of cholesterol esters. These combined findings support the postulate put forward by Langner et al. that fld/fld peripheral neuropathy involves "dysmyelination and concomitant demyelination" (Langner et al., 1991). In light of the role of insulin in Schwann cell and adipocyte differentiation and metabolism, it is noteworthy that fld/fld mice have been found to have altered insulin responsiveness (Klingenspor et al., 1999).

The fld critical region was fine-mapped to a 0.42 cM interval on chromosome 12. RT-PCR of liver extracts from 6- and 21-day-old pups revealed an absence in fld/fld liver of transcript from one of the genes in this interval, formerly called Kiaa0188, now known to be the gene encoding lipin. (Peterfy et al. 1999; Peterfy et al. 2001)

fld^2J is a spontaneous point mutation in Lpin1 which occurred on C3H/HeJ in 1994. An unstable gait and tremor by 3 weeks of age was initially observed. An allele test with the original fld mutation was positive. Histological examination shows peripheral neuropathy. The pups have a fatty liver before reaching wean age. As with the original mutation of fld, homozygous femal es will breed and raise their litters. Homozygous males have not been bred.

Development
This spontaneous mutation occurred on C3H/HeJ at The Jackson Laboratory in 1994. It was bred twice by ovarian transplant crossed with a C3FeLe.B6-a male, and has been maintained by sibling mating since then. No non-agouti has been introduced since those early crosses to C3FeLe.B6-a and no black mice have seen in this colony since March, 1995. (1/25/01 MB).

Control Information

	Control
	Heterozygote from the colony
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Lpin1

002533	B6 x BALB/cByJ-Lpin1fld/J
001592	BALB/cByJ-Lpin1fld/J

View Strains carrying other alleles of Lpin1     (2 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Myoglobinuria, Acute Recurrent, Autosomal Recessive   (LPIN1)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Lpin1^fld-2J/Lpin1^fld-2J

        C3H/HeJ-Lpin1^fld-2J/J

• adipose tissue phenotype
• abnormal adipose tissue amount
  • diminished adipose tissue amount, with 50-90% reductions in white and brown fat pad mass   (MGI Ref ID J:66739)
• • decreased brown adipose tissue amount   (MGI Ref ID J:66739)
  • decreased white adipose tissue amount   (MGI Ref ID J:66739)
• abnormal fat cell morphology
  • adipocytes appear immature with small heterozgenous lipid droplets   (MGI Ref ID J:66739)
• • decreased brown fat cell lipid droplet size   (MGI Ref ID J:66739)
  • decreased white fat cell lipid droplet size   (MGI Ref ID J:66739)
• homeostasis/metabolism phenotype
• decreased circulating leptin level
  • plasma leptin levels are significantly reduced   (MGI Ref ID J:66739)
• insulin resistance   (MGI Ref ID J:66739)
• behavior/neurological phenotype
• abnormal gait
  • unstable gait observed by 3 weeks of age   (MGI Ref ID J:66739)
• tremors
  • observed by 3 weeks of age   (MGI Ref ID J:66739)
• liver/biliary system phenotype
• enlarged liver   (MGI Ref ID J:66739)
• hepatic steatosis
  • considerable fatty infiltration is found in newborns   (MGI Ref ID J:66739)
• nervous system phenotype
• peripheral nervous system degeneration
  • histology reveals peripheral neuropathy after 4 weeks of age   (MGI Ref ID J:66739)
• reproductive system phenotype
• male infertility   (MGI Ref ID J:66739)

View Research Applications

Research Applications

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

Lpin1^fld-2J related

Cardiovascular Research
Hypertriglyceridemia

Dermatology Research
Skin and Hair Texture Defects

Developmental Biology Research
Growth Defects
Internal/Organ Defects
      liver
Neurodevelopmental Defects
Postnatal Lethality

Diabetes and Obesity Research
Hyperinsulinemia
      moderate
Impaired Insulin Processing
Insulin Resistance

Endocrine Deficiency Research
Adipose Defects

Internal/Organ Research
Adipose Defects
Liver Defects

Metabolism Research
Lipid Metabolism

Neurobiology Research
Ataxia (Movement) Defects
Metabolic Defects
Myelination Defects
      peripheral neuropathy
Neurodegeneration
Neurodevelopmental Defects
Tremor Defects

Reproductive Biology Research
Fertility Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Lpin1fld-2J
Allele Name		fatty liver dystrophy 2 Jackson
Allele Type		Spontaneous
Common Name(s)		fld2J;
Strain of Origin		C3H/HeJ
Gene Symbol and Name		Lpin1, lipin 1
Chromosome		12
Gene Common Name(s)		Lipin1; PAP1; fatty liver dystrophy; fld; mKIAA0188;
General Note		This remutation arose at the Jackson Laboratory in 1998, and was found to be an allele of Lpin1fld. Heterozygotes for the new mutation and for Lpin1fld produced 6 affected mice of 10 born. PCR for markers on chromosome 12 further confirmed the allelism test. Similar to the original Lpin1fld mutant mouse, affected newborns have an enlarged liver that normalizes by weaning. Homozygotes develop an unsteady gait and tremor by three weeks of age. Female homozygotes breed, but homozygous males have not been bred. Pathological examination of liver from newborns revealed fatty infiltration as in the original fld mutation and peripheral neuropathy was found in affected mice from four weeks onward (J:51014, J:51188).
Molecular Note		A G-to-A transition mutation in codon 84 is predicted to alter this residue from a glycine to an arginine in the encoded protein. This position corresponds to the NLIP domain of the protein and is highly conserved in other species. [MGI Ref ID J:66739]

Genotyping

Genotyping Information

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Additional References

Klingenspor M; Xu P; Cohen RD; Welch C; Reue K. 1999. Altered gene expression pattern in the fatty liver dystrophy mouse reveals impaired insulin-mediated cytoskeleton dynamics. J Biol Chem 274(33):23078-84. [PubMed: 10438476]  [MGI Ref ID J:42314]

Langner CA; Birkenmeier EH; Ben-Zeev O; Schotz MC; Sweet HO; Davisson MT; Gordon JI. 1989. The fatty liver dystrophy (fld) mutation. A new mutant mouse with a developmental abnormality in triglyceride metabolism and associated tissue-specific defects in lipoprotein lipase and hepatic lipase activities. J Biol Chem 264(14):7994-8003. [PubMed: 2722772]  [MGI Ref ID J:9801]

Langner CA; Birkenmeier EH; Roth KA; Bronson RT; Gordon JI. 1991. Characterization of the peripheral neuropathy in neonatal and adult mice that are homozygous for the fatty liver dystrophy (fld) mutation. J Biol Chem 266(18):11955-64. [PubMed: 2050689]  [MGI Ref ID J:82882]

Peterfy M; Phan J; Xu P; Reue K. 2001. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin Nat Genet 27(1):121-4. [PubMed: 11138012]  [MGI Ref ID J:66739]

Rehnmark S; Giometti CS; Slavin BG; Doolittle MH; Reue K. 1998. The fatty liver dystrophy mutant mouse: microvesicular steatosis associated with altered expression levels of peroxisome proliferator-regulated proteins. J Lipid Res 39(11):2209-17. [PubMed: 9799807]  [MGI Ref ID J:50756]

Reue K; Doolittle MH. 1996. Naturally occurring mutations in mice affecting lipid transport and metabolism. J Lipid Res 37(7):1387-405. [PubMed: 8827513]  [MGI Ref ID J:34179]

Reue K; Xu P; Wang XP; Slavin BG. 2000. Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene J Lipid Res 41(7):1067-76. [PubMed: 10884287]  [MGI Ref ID J:63448]

Lpin1^fld-2J related

Donahue LR. 1999. The Jackson Laboratory Mouse Mutant Resource 1999 Mutation Reports MGI Direct Data Submission :.  [MGI Ref ID J:51014]

Peterfy M; Phan J; Xu P; Reue K. 2001. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin Nat Genet 27(1):121-4. [PubMed: 11138012]  [MGI Ref ID J:66739]

Samples R. 1999. The Jackson Laboratory Mouse Mutant Resource 1999 Mutation Reports MGI Direct Data Submission :.  [MGI Ref ID J:51188]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

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

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Heterozygote from the colony
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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.

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