FROM LOCUS TO CELLULAR DISTURBANCES - POSITIONAL CLONING OF THE INFANTILE NEURONAL CEROID-LIPOFUSCINOSIS GENE

Neuronal ceroid lipofuscinoses (NCL) represent a group of common progr essive encephalopathies of children with a global incidence of 1 in 12 ,500. NCL are divided into three autosomal recessive subtypes, all ass igned to different chromosomal loci. The infantile subtype of NCL (INC L) is characterized by early visual toss and mental deterioration, and leads to a vegetative state of the patients by 3 years of age. We pur sued the identification of the gene defective in INCL, enriched in the Finnish population by a positional cloning approach and identified mu tations in the palmitoyl-protein thioesterase (PPT) gene in INCL patie nts. We have further shown that PPT represents a novel lysosomal enzym e and is routed to the lysosomes via the mannose 6-phosphate receptor- mediated pathway. The worldwide most common mutation in the PPT gene, INCLFin, results in the deficient routing of the mutant PPT to lysosom es and undetectable enzyme activity in the brain tissue of patients. O ur results suggest that INCL can be classified as a new member of lyso somal enzyme deficiencies.