A Novel Mannose 6-phosphate Specific Antibody Fragment for Diagnosis of Mucolipidosis type II and III

Eukaryotic cells of animals have developed a specialized organelle for the degradation and recycling of macromolecules, called the lysosome (De Duve 1963). The breakdown of these macromolecules is carried out by more than 60 acid hydrolases such as proteases, nucleases, glycosidases, phosphatases, lipases etc. (Luzio et al. 2007). Newly synthesized lysosomal hydrolases are equipped with mannose 6-phosphate (Man6P) residues on high-mannose type N-glycans. This marker is generated in the Golgi apparatus in a two-step enzymatic process in which first a N-acetylglucosamine 1-phosphate (GlcNAc1P) residue is transferred to a terminal mannose (Man) residue. In a second step the enzymatic hydrolysis of the GlcNAc uncovers the Man6P residue. Man6P functions as recognition marker for specific receptors required for lysosomal targeting of acid hydrolases. Importantly, from a medical point of view, also extracellular Man6P-containing proteins can be internalized and transported to the lysosomes via Man6P-receptors which are located also at the plasma membrane (Kornfeld and Mellman 1989; Braulke and Bonifacino 2009). Whereas the majority of the over 50 known lysosomal storage disorders are caused by inherited defects of single lysosomal enzymes or lysosomal membrane proteins, the failure to generate Man6P leads to a deficiency of multiple enzymes resulting in mucolipidosis (ML) type II and type III (Futerman and van Meer 2004).