Molecular and phenotypic analysis of Attractin mutant mice

Mutations Of the mouse Attractin (Atrn; formerly mahogany) gene were origin ally recognized because they suppress Agouti pigment type switching. More r ecently, effects independent of Agouti have been recognized: mice homozygou s for the Atrn(mg3J) allele are resistant to diet-induced obesity and also develop abnormal myclination and vacuolation in the central nervous system. To better understand the pathophysiology and relationship of these pleiotr opic effect,, we further characterized the molecular abnormalities responsi ble for two additional Atrn alleles, Atrn(25g) and Atrn(mg-L), and examined in parallel die phenotypes of homozygous and compound heterozygous animals . We find that the three alleles have similar effects on pigmentation and n eurodegeneration, with a relative severity of Atrn(mg-3J) > Atrn(mg) > Atrn (mg-L), which also corresponds to the effects of the three alleles on level s of normal Atrn mRNA. Animals homozygous for Atrn(mg-3J) or Atrn(mg), but not Atrn(mg-L), show reduced body weight, reduced adiposity, and increased locomotor activity, all in the presence of normal food intake. These result s confirm that the mechanism responsible for the neuropathological alterati on is a loss-rather than gain-of function, indicate that abnormal body weig ht in Atrn mutant mice is caused by a central process leading to increased energy expenditure, and demonstrate that pigmentation is more sensitive to levels of Atrn mRNA than are nonpigmentary phenotypes.