Importance of the Glycosylation and Polyadenylation Variants in Metachromatic Leukodystrophy Pseudodeficiency Phenotype

• Published in: Human molecular genetics Vol. 7; no. 8; pp. 1215 - 1219
• Main Authors: Harvey, John S., Carey, William F., Morris, C. Phillip
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-08-1998
• Subjects: Adenosine Monophosphate; Alleles; Amino Acid Substitution; Biological and medical sciences; Cerebroside-Sulfatase - genetics; Cerebroside-Sulfatase - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Glycosylation; Homozygote; Humans; Leukodystrophy, Metachromatic - enzymology; Leukodystrophy, Metachromatic - genetics; Medical sciences; Neurology; Human; Cerebroside-sulfatase; Metachromatic leukodystrophy; Nervous system diseases; Enzyme; Genetic variant; Lipids; Metabolic diseases; Esterases; Glycosylation; Sphingolipidosis; Gene expression; Enzymopathy; Genetic disease; Phenotype; Gene; Central nervous system disease; Polyadenylation; Hydrolases; Genetics; Degenerative disease; Mutation; Sulfuric ester hydrolases; Lipoidosis
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/7.8.1215

Metachromatic leukodystrophy (MLD) is an inborn error of myelin metabolism caused by a deficiency of the lysosomal hydrolase, arylsulfatase A (ASA). About 1% of the normal population have ASA activity levels approximating those of MLD patients. This non-pathogenic reduction in ASA activity is caused by homozygosity for the ASA pseudodeficiency allele (ASA-PD). Although this al-lele contains two sequence alterations, a polyadenyla-tion defect and an amino acid substitution (N350S), the reduction in ASA activity previously has been attributed to the polyadenylation defect which reduces the amount of ASA mRNA and hence ASA protein by ∼90%. The identification of MLD patients who are homozygous for the ASA-PD allele has brought about the need to re-evaluate the allele in light of the possible role that it may play in the development and progression of disease. Ribonuclease protection assay analysis of ASA mRNA transcripts and an investigation into the activity and lysosomal localization of protein expressed by an ASA expression construct containing the N350S variant indicated that both the N350S and polyadenylation defects play a role in biochemically defining the ASA-PD phenotype. The combined effect of the reduction in ASA mRNA due to the polyadenylation defect and the lowering of ASA activity and aberrant targeting of the expressed N350S ASA protein to the lysosome is estimated to reduce ASA activity in pseudodeficiency homozygotes to ∼8% of normal.