title: A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat.
abstract: 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.
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands.
authors.forename: Joram D
authors.initials: JD
authors.lastname: Mul
authors.forename: Karim
authors.initials: K
authors.lastname: Nadra
authors.forename: Noorjahan B
authors.initials: NB
authors.lastname: Jagalur
authors.forename: Isaac J
authors.initials: IJ
authors.lastname: Nijman
authors.forename: Pim W
authors.initials: PW
authors.lastname: Toonen
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Médard
authors.forename: Sandra
authors.initials: S
authors.lastname: Grès
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.forename: Gil-Soo
authors.initials: GS
authors.lastname: Han
authors.forename: Jos F
authors.initials: JF
authors.lastname: Brouwers
authors.forename: George M
authors.initials: GM
authors.lastname: Carman
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Saulnier-Blache
authors.forename: Dies
authors.initials: D
authors.lastname: Meijer
authors.forename: Roman
authors.initials: R
authors.lastname: Chrast
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D003711:Demyelinating Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005038:Ethylnitrosourea / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007438:Introns; D008060:Lipodystrophy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016296:Mutagenesis; D009154:Mutation; D000073718:Pancreatitis-Associated Proteins; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D022821:RNA Splice Sites; D051381:Rats; D011922:Rats, Mutant Strains
chemical_list: D000477:Alkylating Agents; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D022821:RNA Splice Sites; D010711:Phosphatidate Phosphatase; D005038:Ethylnitrosourea