A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2

J Biol Chem. 2009 Oct 23;284(43):29968-78. doi: 10.1074/jbc.M109.023663. Epub 2009 Aug 28.


Mammalian lipins (lipin-1, lipin-2, and lipin-3) are Mg2+-dependent phosphatidate phosphatase (PAP) enzymes, which catalyze a key reaction in glycerolipid biosynthesis. Lipin-1 also functions as a transcriptional coactivator in conjunction with members of the peroxisome proliferator-activated receptor family. An S734L mutation in LPIN2 causes Majeed syndrome, a human inflammatory disorder characterized by recurrent osteomyelitis, fever, dyserythropoietic anemia, and cutaneous inflammation. Here we demonstrate that mutation of the equivalent serine in mouse lipin-1 and lipin-2 to leucine or aspartate abolishes PAP activity but does not impair lipin association with microsomal membranes, the major site of glycerolipid synthesis. We also determined that lipin-2 has transcriptional coactivator activity for peroxisome proliferator-activated receptor-response elements similar to lipin-1 and that this activity is not affected by mutating the conserved serine. Therefore, our results indicate that the symptoms of the Majeed syndrome result from a loss of lipin-2 PAP activity. To characterize sites of lipin-2 action, we detected lipin-2 expression by in situ hybridization on whole mouse sections and by quantitative PCR of tissues relevant to Majeed syndrome. Lipin-2 was most prominently expressed in liver, where levels were much higher than lipin-1, and also in kidney, lung, gastrointestinal tract, and specific regions of the brain. Lipin-2 was also expressed in circulating red blood cells and sites of lymphopoiesis (bone marrow, thymus, and spleen). These results raise the possibility that the loss of lipin-2 PAP activity in erythrocytes and lymphocytes may contribute to the anemia and inflammation phenotypes observed in Majeed syndrome patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Anemia, Dyserythropoietic, Congenital / enzymology
  • Anemia, Dyserythropoietic, Congenital / genetics
  • Animals
  • Cell Line
  • Dermatitis / enzymology
  • Dermatitis / genetics
  • Fever / enzymology
  • Fever / genetics
  • Gene Expression Regulation, Enzymologic / genetics
  • Humans
  • Mice
  • Mutation, Missense
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Organ Specificity / genetics
  • Osteomyelitis / enzymology
  • Osteomyelitis / genetics
  • Peroxisome Proliferator-Activated Receptors
  • Phosphatidate Phosphatase / genetics
  • Phosphatidate Phosphatase / metabolism*
  • Response Elements
  • Serine / genetics
  • Serine / metabolism*
  • Syndrome


  • LPIN2 protein, human
  • Nuclear Proteins
  • Peroxisome Proliferator-Activated Receptors
  • Serine
  • LPIN1 protein, human
  • Lpin1 protein, mouse
  • Phosphatidate Phosphatase
  • Lipin 2 protein, mouse