J. Biol. Chem., Vol. 266, Issue 32, 21386-21391, 11, 1991
Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). An intermediate clinical phenotype caused by substitution of valine for glycine at position 137 of arylsulfatase B
G Wicker, V Prill, D Brooks, G Gibson, J Hopwood, K von Figura and C Peters
Universitat Gottingen, Federal Republic of Germany.
The Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI) is a lysosomal
storage disease with autosomal recessive inheritance caused by deficiency
of the enzyme arylsulfatase B. Severe, intermediate, and mild forms of the
disease have been described. The molecular correlate of the clinical
heterogeneity is not known at present. To identify the molecular defect in
a patient with the intermediate form of the disease, arylsulfatase B mRNA
from his fibroblasts was reverse- transcribed, amplified by the polymerase
chain reaction, and subcloned. Three point mutations were detected by DNA
sequence analysis, two of which, a silent A to G transition at nucleotide
1191 and a G to A transition at nucleotide 1126 resulting in a methionine
for valine 376 substitution, were polymorphisms. A G to T transversion at
nucleotide 410 causing a valine for glycine 137 substitution (G137V) was
identified as the mutation underlying the Maroteaux-Lamy phenotype of the
patient, who was homozygous for the allele. The kinetic parameters of the
mutant arylsulfatase B enzyme toward a radiolabeled trisaccharide substrate
were normal excluding an alteration of the active site. The G137V mutation
did not affect the synthesis but severely reduced the stability of the
arylsulfatase B precursor. While the wild type precursor is converted by
limited proteolysis in late endosomes or lysosomes to a mature form, the
majority of the mutant precursor was degraded presumably in a compartment
proximal to the trans Golgi network and only a small amount escaped to the
lysosomes accounting for the low residual enzyme activity in fibroblasts of
a patient with the juvenile form of the disease.
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