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.