IMPORTANCE OF THE GLYCOSYLATION AND POLYADENYLATION VARIANTS IN METACHROMATIC LEUKODYSTROPHY PSEUDODEFICIENCY PHENOTYPE

Metachromatic leukodystrophy (MLD) is an inborn error of myelin metabo lism caused by a deficiency of the lysosomal hydrolase, arylsulfatase A (ASA). About 1% of the normal population have ASA activity levels ap proximating those of MLD patients. This non-pathogenic reduction in AS A activity is caused by homozygosity for the ASA pseudodeficiency alle le (ASA-PD). Although this allele contains two sequence alterations, a polyadenylation defect and an amino acid substitution (N350S), the re duction in ASA activity previously has been attributed to the polyaden ylation defect which reduces the amount of ASA mRNA and hence ASA prot ein by similar to 90%. The identification of MLD patients who are homo zygous for the ASA-PD allele has brought about the need to reevaluate the allele in light of the possible role that it may play in the devel opment and progression of disease, Ribonuclease protection assay analy sis of ASA mRNA transcripts and an investigation into the activity and lysosomal localization of protein expressed by an ASA expression cons truct containing the N350S variant indicated that both the N350S and p olyadenylation defects play a role in biochemically defining the ASA-P D phenotype, The combined effect of the reduction in ASA mRNA due to t he polyadenylation defect and the lowering of ASA activity and aberran t targeting of the expressed N350S ASA protein to the lysosome is esti mated to reduce ASA activity in pseudodeficiency homozygotes to simila r to 8% of normal.