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

Summary

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, ASA_p, is known. On SDS-PAGE the ASA_p enzyme migrates slightly faster than ASA⁺. Treatment of extracts from cells with ASA⁺/ASA⁺, ASA_p/ASA_p, or ASA⁺/ASA_p genotypes with endoglycosidase F leads to the same deglycosylated subunit pattern. Presumably the degree of glycosylation is lower in ASA_p than in ASA⁺. In a large-scale screening project we determined a gene frequency of 7.3% for ASA_p. Thus, the ASA locus is polymorphic. In seven families, ASA_p showed a codominant mode of inheritance with ASA⁺. Homozygosity for ASA_p has no obvious clinical consequences. In subjects with the compound genotype ASA^-/ASA_p, 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.