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 a...
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)
fld2J 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.
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).
|Allele Name||fatty liver dystrophy 2 Jackson|
|Gene Symbol and Name||Lpin1, lipin 1|
|Gene Synonym(s)||Lipin1; PAP1; fatty liver dystrophy; fld; mKIAA0188|
|Strain of Origin||C3H/HeJ|
|General Note||This remutation arose at the Jackson Laboratory in 1998. |
Phenotypic Similarity to Human Syndrome: Lipodystrophy in homozygous mice (J:66739)
|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.|
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