NAGLU mutations underlying Sanfilippo syndrome type B.

Sanfilippo syndrome type B (mucopolysaccharidosis III B) is a rare autosomal recessive disease caused by deficiency of alpha-N-acetylglucosaminidase, one of the enzymes required for the lysosomal degradation of heparan sulfate. The gene for this enzyme, NAGLU, recently was isolated, and several mutations were characterized. We have identified, in amplified exons from nine fibroblast cell lines derived from Sanfilippo syndrome type B patients, 10 additional mutations: Y92H, P115S, Y140C, E153K, R203X, 650insC, 901delAA, P358L, A664V, and L682R. Four of these mutations were found in homozygosity, and only two were seen in more than one cell line. Thus, Sanfilippo syndrome type B shows extensive molecular heterogeneity. Stable transfection of Chinese hamster ovary cells, by cDNA mutagenized to correspond to the NAGLU missense mutations, did not yield active enzyme, demonstrating the deleterious nature of the mutations. Nine of the 10 amino acid substitutions identified to date are clustered near the amino or the carboxyl end of alpha-N-acetylglucosaminidase, suggesting a role for these regions in the transport or function of the enzyme.