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.,
Journal of Biological Chemistry
Erasmus MC: University Medical Center Rotterdam

Mul, J., Nadra, K., Jagalur, N., Nijman, I., Toonen, P., 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