The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat model with a mutated Lpin1 gene (Lpin11Hubr), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin11Hubrrats are characterized by hindlimb paralysis and mild lipodystrophy that are detectable from the second postnatal week. Sequencing of Lpin1 identified a point mutation in the 5′-end splice site of intron 18 resulting in missplicing, a reading frameshift, and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. Lpin11Hubrrats developed hypomyelination and mild lipodystrophy rather than the pronounced demyelination and adipocyte defects characteristic of Lpin1fld/fldmice, which carry a null allele for Lpin1. Furthermore, biochemical, histological, and molecular analyses revealed that these lesions improve in older Lpin11Hubrrats as compared with young Lpin11Hubrrats and Lpin1fld/fldmice. We observed activation of compensatory biochemical pathways substituting for missing PAP1 activity that, in combination with a possible non-enzymatic Lipin 1 function residing outside of its PAP1 domain, may contribute to the less severe phenotypes observed in Lpin11Hubrrats as compared with Lpin1fld/fldmice. Although we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into the pathogenicity of recently identified human LPIN1 mutations.

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Journal Journal of Biological Chemistry
Mul, J.D, Nadra, K, Jagalur, N.B, Nijman, I.J, Toonen, P.W, Médard, J.J, … Cuppen, E. (2011). A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat. Journal of Biological Chemistry, 286(30), 26781–26793. doi:10.1074/jbc.M110.197947