TARGETED DISRUPTION OF THE M(R) 46-000 MANNOSE 6-PHOSPHATE RECEPTOR GENE IN MICE RESULTS IN MISROUTING OF LYSOSOMAL PROTEINS

Lysosomal enzymes containing mannose 6-phosphate recognition markers a re sorted to lysosomes by mannose 6-phosphate receptors (MPRs). The ph ysiological importance of this targeting mechanism is illustrated by I -cell disease, a fatal lysosomal storage disorder caused by the absenc e of mannose 6-phosphate residues in lysosomal enzymes. Most mammalian cells express two MPRs. Although the binding specificities, subcellul ar distribution and expression pattern of the two receptors can be dif ferentiated, their coexpression is not understood. The larger of the t wo receptors with an M(r) of approximately 300 000 (MPR300), which als o binds IGFII, appears to have a dominant role in lysosomal enzyme tar geting, while the function of the smaller receptor with an M(r) Of 46 000 (MPR46) is less clear. To investigate the in vivo function of the MPR46, we generated MPR46-deficient mice using gene targeting in embry onic stem cells. Reduced intracellular retention of newly synthesized lysosomal proteins in cells from MPR46 - / - mice demonstrated an esse ntial sorting function of MPR46. The phenotype of MPR46 - / - mice was normal, indicating mechanisms that compensate the MPR46 deficiency in vivo.