Characterization of four arylsulfatase A missense mutations G86D, Y201C, D255H, and E312D causing metachromatic leukodystrophy

Metachromatic leukodystrophy is a lysosomal storage disease caused by the d eficiency of arylsulfatase A. Here we describe a hitherto unknown arylsulfa tase A allele carrying a E312D missense mutation and characterize the effec ts of this and three previously described missense mutations, G86D, Y201C, and D255H, on arylsulfatase A. In transfection experiments no enzyme activi ty can be expressed from arylsulfatase A cDNAs coding for the D255H substit uted enzyme, whereas Y201C and E312D mutations were associated with low amo unts of residual enzyme activity. All amino acid substitutions lead to a de creased stability of the mutant enzyme, and metabolic labeling experiments indicated that except for the E312D substitution the mutations cause arrest of the mutant arylsulfatase A polypeptides in a prelysosomal compartment. (C) 2000 Wiley-Liss, Inc.