FREQUENCY OF ARYLSULFATASE-A PSEUDODEFICIENCY ASSOCIATED MUTATIONS INA HEALTHY POPULATION

Arylsulphatase A (ASA, EC3.1.6.1) is a lysosomal enzyme that catalyses cerebroside sulphate degradation. ASA deficiency is associated with m etachromatic leucodystrophy (MLD), a rare autosomal recessive disorder , which is characterised by the storage of cerebroside sulphate. Low A SA activities can be also observed in clinically healthy persons, a co ndition termed ASA pseudodeficiency. Two mutations responsible for the majority of pseudodeficiency alleles have been defined in the ASA gen e. These are both A --> G transitions. One causes an asparagine to ser ine substitution (N350S). The second changes the first polyadenylation signal downstream of the stop codon (1524 + 95 A --> G), which causes a severe deficiency of one ASA mRNA species. The incidence of the pse udodeficiency allele is estimated to be high in the general population and can be found in families carrying MLD associated mutations. We re port a reliable stratagem for detecting the two PD associated mutation s separately, which we have applied to a healthy population. Two homoz ygotes for the N350S and 1524 + 95 A --> G mutations were detected, wh ich gives a population frequency of 2.6%. The overall frequencies of t he ASA-PD mutations were shown to be 17.5% for the N350S change and 13 .0% for the 1524 + 95 A --> G change, estimating each mutation separat ely. In addition, the frequency of both PD associated mutations occurr ing together on the same chromosome was found to be 12.3% in our popul ation. The study has also allowed us to establish a new control ASA ac tivity range, which was based on assay of blood from persons who had b een shown at the DNA level not to carry ASA PD associated mutations.