Pseudodeficiency of arylsulfatase A: a common genetic polymorphism with possible disease implications

Abstract

At the locus for arylsulfatase A (ASA) at least four to five alleles exist: besides the normal ASA+ and at least two to three deficiency alleles (ASA-), a pseudodeficiency allele, ASAp, is known. On SDS-PAGE the ASAp enzyme migrates slightly faster than ASA+. Treatment of extracts from cells with ASA+/ASA+, ASAp/ASAp, or ASA+/ASAp genotypes with endoglycosidase F leads to the same deglycosylated subunit pattern. Presumably the degree of glycosylation is lower in ASAp than in ASA+. In a large-scale screening project we determined a gene frequency of 7.3% for ASAp. Thus, the ASA locus is polymorphic. In seven families, ASAp showed a codominant mode of inheritance with ASA+. Homozygosity for ASAp has no obvious clinical consequences. In subjects with the compound genotype ASA-/ASAp, the residual enzyme activity may fall below a critical threshold, so that the substrate can no longer be hydrolyzed sufficiently. Since these compounds are not so rare (estimated frequency 0.073%), this mechanism could be of importance in neuropsychiatric disorders with late onset.

Arylsulfatase A pseudodeficiency: loss of a polyadenylylation signal and N-glycosylation site.

“…A 6-kb ASA genomic clone containing the entire ASA gene was isolated from a library made from size-selected genomic DNA of an individual homozygous for ASA pseudodeficiency allele (5). Knowledge of the ASA cDNA sequence and of the intron-exon organization of the ASA gene (J.K., unpublished work) allowed the sequencing of the exons that contain the potential N-glycosylation sites.…”

“…The high frequency of the ASA pseudodeficiency allele of 7-15% (5,6) and the inability to distinguish reliably homoand heterozygotes for nonfunctional and pseudodeficiency ASA alleles by ASA activity determinations with artificial or natural substrates pose serious problems in the genetic counseling and prenatal diagnosis of metachromatic leukodystrophy (7). Thus, the availability of allele-specific tests would facilitate genetic counseling and pre-and postnatal diagnosis in families at risk for metachromatic leukodystrophy.…”

Biochemical Basis of Late-Onset Neurolipidoses

“…Pseudodefi ciency o f a lysosomal enzyme is much more frequent than previously thought and may pose a serious diagnos tic problem, particularly for prenatal diagnosis. In Cen tral Europe, approximately 1 in 200 persons is estimated to be homozygous for ASA pseudodeficiency [4] and a large number o f atypical MLD patients with some other,' unrelated neurologic disease are probably misdiagnosed pseudodeficient probands [5,6].…”

Innovative Therapeutic Approaches for Improving Patient Life Condition with a Neurological Lysosomal Disease

“…Two mutant alleles are particularly frequent and account each for about 25% of mutant alleles among Caucasian patients (Polten et al, 1991;Barth et al, 1993). Deficiency of arylsulfatase A has also been demonstrated in healthy individuals at high frequency (up to 2.6% of the population) (Barth et al, 1993;Hohenschutz et al, 1989). The deficiency is substantial, but since it is not complete it does not cause a disease and is another example of lysosomal enzyme pseudodeficiency (Dubois et al, 1977).…”