RGD Reference Report - A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat. - Rat Genome Database

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A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat.

Authors: Mul, Joram D  Nadra, Karim  Jagalur, Noorjahan B  Nijman, Isaac J  Toonen, Pim W  Médard, Jean-Jacques  Grès, Sandra  de Bruin, Alain  Han, Gil-Soo  Brouwers, Jos F  Carman, George M  Saulnier-Blache, Jean-Sébastien  Meijer, Dies  Chrast, Roman  Cuppen, Edwin 
Citation: Mul JD, etal., J Biol Chem. 2011 Jul 29;286(30):26781-93. doi: 10.1074/jbc.M110.197947. Epub 2011 Jun 1.
RGD ID: 38599010
Pubmed: PMID:21715287   (View Abstract at PubMed)
PMCID: PMC3143639   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M110.197947   (Journal Full-text)

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 (Lpin1(1Hubr)), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin1(1Hubr) rats 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 mis-splicing, 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. Lpin1(1Hubr) rats developed hypomyelination and mild lipodystrophy rather than the pronounced demyelination and adipocyte defects characteristic of Lpin1(fld/fld) mice, which carry a null allele for Lpin1. Furthermore, biochemical, histological, and molecular analyses revealed that these lesions improve in older Lpin1(1Hubr) rats as compared with young Lpin1(1Hubr) rats and Lpin1(fld/fld) mice. 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 Lpin1(1Hubr) rats as compared with Lpin1(fld/fld) mice. 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.



Gene Ontology Annotations    

Phenotype Annotations    

Mammalian Phenotype
Objects Annotated

Genes (Rattus norvegicus)
Lpin1  (lipin 1)
Lpin1m1Hubr  (lipin 1; ENU induced mutant 1, Hubr)

Strains
WI-Lpin1m1Hubr  (NA)


Additional Information