UNDERSTANDING THE MOLECULAR BASIS OF MUCOLIPIDOSIS TYPE IV

Mucolipidosis type IV (MLIV, MIM 252650) is an autosomal recessive lysosomal storage disorder characterized by severe psychomotor retardation and ophthalmological abnormalities, including cornea opacity, retinal degeneration, and strabismus. Patients from over seventy families have been described; more than 90% of them are Ashkenazi Jewish. Unlike other lysosomal disorders, the accumulation of heterogeneous storage material observed in MLIV does not result from a block in the catabolic pathways, but is due to an ill-defined transport defect in the late steps of endocytosis. We have recently identified a novel gene which is mutated in all MLIV patients enrolled in our study. The gene, ML4, encodes a protein named mucolipidin which localizes on the plasma membrane and shows homologies to polycystin-2, the product of the polycystic kidney disease 2 gene (PKD2) and to the family of transient receptor potential Ca2+ channels (TRPC). We propose to study the molecular basis of the MLIV disorder, using a combination of experimental approaches which include the attempt to rescue the altered cellular phenotype of MLIV fibroblasts through the delivery of the wild-type ML4 gene. These studies will be particularly useful to dissect the pathogenetic mechanism underlying this complex metabolic disorder. Furthermore they will provide valuable resources for both the identification and the development of specific therapeutic approaches.