Journal Article

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

John S. Harvey, William F. Carey and C. Phillip Morris

in Human Molecular Genetics

Volume 7, issue 8, pages 1215-1219
Published in print August 1998 | ISSN: 0964-6906
Published online August 1998 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/7.8.1215
Importance of the Glycosylation and Polyadenylation Variants in Metachromatic Leukodystrophy Pseudodeficiency Phenotype

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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.

Journal Article.  3656 words.  Illustrated.

Subjects: Genetics and Genomics

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