NAGLU MUTATIONS UNDERLYING SANFILIPPO SYNDROME TYPE-B

Sanfilippo syndrome type B (mucopolysaccharidosis III B) is a rare aut osomal recessive disease caused by deficiency of alpha-N-acetylglucosa minidase, one of the enzymes required for the lysosomal degradation of heparan sulfate. The gene for this enzyme, NAGLU, recently was isolat ed, and several mutations were characterized. We have identified, in a mplified exons from nine fibroblast cell lines derived from Sanfilippo syndrome type B patients, 10 additional mutations: Y92H, P115S, Y140C , E153K, R203X, 650insC, 901delAA, P358L, AG64V, and L682R. Four of th ese mutations were found in homozygosity, and only two were seen in mo re than one cell line. Thus, Sanfilippo syndrome type B shows extensiv e molecular heterogeneity. Stable transfection of Chinese hamster ovar y cells, by cDNA mutagenized to correspond to the NAGLU missense mutat ions, did not yield active enzyme, demonstrating the deleterious natur e 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-a cetylglucosaminidase, suggesting a role for these regions in the trans port or function of the enzyme.