MUCOPOLYSACCHARIDOSIS-VI (MAROTEAUX-LAMY SYNDROME) - 6 UNIQUE ARYLSULFATASE-B GENE ALLELES CAUSING VARIABLE DISEASE PHENOTYPES

Mucopolysaccharidosis type VI, or Maroteaux-Lamy syndrome, is a lysoso mal storage disorder caused by a deficiency of the enzyme arylsulfatas e B (ASB), also known as N-acetylgalactosamine-4-sulfatase. Multiple c linical phenotypes of this autosomal recessively inherited disease hav e been described. Recent isolation and characterization of the human A SB gene facilitated the analysis of molecular defects underlying the d ifferent phenotypes. Conditions for PCR amplification of the entire op en reading frame from genomic DNA and for subsequent direct automated DNA sequencing of the resulting DNA fragments were established. Beside s two polymorphisms described elsewhere that cause methionine-for-vali ne substitutions in the arylsulfatase B gene, six new mutations in six patients were detected: four point mutations resulting in amino acid substitutions, a l-bp deletion, and a 1-bp insertion. The point mutati ons were two G-to-A and two T-to-C transitions. The Gto-A transitions cause an arginine-for-glycine substitution at residue 144 in a homoall elic patient with a severe disease phenotype and a tyrosine-for-cystei ne substitution at residue 521 in a potentially heteroallelic patient with the severe form of the disease. The T-to-C transitions cause an a rginine-for-cysteine substitution at amino acid residue 192 in a homoa llelic patient with mild symptoms and a proline-for-leucine substituti on at amino acid 321 in a homoallelic patient with the intermediate fo rm. The insertion between nucleotides T1284 and G1285 resulted in a lo ss of the 100 C-terminal amino acids of the wild-type protein and in t he deletion of nucleotide C1577 in a 33-amino-acid C-terminal extensio n of the ASB polypeptide. Both mutations were detected in homoallelic patients with the severe form of the disease. Expression of mutant cDN As encoding the four amino acid substitutions and the deletion resulte d in severe reduction of both ASB protein levels and arylsulfatase enz yme activity in comparison with a wild-type control. The six mutations described in the present study were unique among 25 unrelated mucopol ysaccharidosis VI patients, suggesting a broad molecular heterogeneity of the Maroteaux-Lamy syndrome.