Canine heparan sulfate sulfamidase and the molecular pathology underlying Sanfilippo syndrome type A in Dachshunds

Heparan sulfate sulfamidase (HSS) is a lysosomal exohydrolase that, when de ficient, results in intralysosomal accumulation of heparan sulfate and the clinical phenotype of Sanfilippo syndrome type A. The first animal disease homolog of human Sanfilippo syndrome type A has been recently indentified i n Dachshund littermates. To identify the molecular defect, the nucleotide s equences of the normal canine HSS gene and cDNA were determined using PCR-b ased approaches. The coding region showed 87% nucleotide homology, and 89% amino acid sequence homology, with human HSS. All exon-intron borders were conserved. Sequence analysis of the entire coding region with exon-intron b oundaries was performed in the propositus, a healthy littermate, and six un related normal dogs. Comparison revealed a 3-bp deletion, 737-739delCCA, re sulting in the loss of threonine at position 246 in both alleles of the pro positus and in one allele of a healthy littermate. Prediction of the three- dimensional structure of canine HSS, based on homology with human arylsulfa tases A and B, suggested the pathogenic effect of this deletion. Six other sequence variations in exons, and 10 in introns, appear to be benign polymo rphisms. This study supports the potential development of a canine model of Sanfilippo syndrome type A to evaluate gene therapy for this disorder, (C) 2000 Academic Press.