COMPLEX ARYLSULFATASE-A ALLELES CAUSING METACHROMATIC LEUKODYSTROPHY

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. Sequencing of the arylsulfatase A genes of a patient affected with late infantile metachromatic leukodys trophy revealed that the patient is a compound heterozygote of two all eles carrying two deleterious mutation each. One allele bears a splice donor site mutation together with two polymorphisms and an additional missense mutation (Gly122>Ser). The splice donor site mutation and th e Gly122>Ser substitution have been described recently but on differen t alleles. The other allele carries two missense mutations causing a G lyl54>Asp and a Pro167>Arg substitution. When arylsulfatase A cDNAs ca rrying these mutations separately or in combination were transfected i nto baby hamster kidney cells expression of arylsulfatase A activity c ould not be detected. Linkage of mutations was verified by sequencing of the parental DNAs. Biosynthesis studies performed with the patients ' fibroblasts show that the enzyme carrying both mutations is synthesi zed in almost normal amounts but is rapidly degraded in an early biosy nthetic compartment. The occurence of two disease causing mutations on the same allele is a novel phenomenon in metachromatic leukodystrophy and as far as lysosomal storage diseases are concerned have so far on ly been described in Fabry disease and in the complex glucocerebrosida se alleles associated with Gaucher disease. (C) 1994 Wiley-Liss, Inc.