Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB).
Sanfilippo syndrome type B (mucopolysaccharidosis IIIB) is an autosomal recessive disease that is caused by the deficiency of the lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). NAGLU is involved in the degradation of the glycosaminoglycan (GAG) heparan sulphate, and a deficiency results in the accumulation of partially degraded GAGs inside lysosomes. Early clinical symptoms include hyperactivity, aggressiveness and delayed development, followed by progressive mental deterioration, although there are a small number of late-onset attenuated cases. The gene for NAGLU has been fully characterized and we report the molecular analysis of 18 Sanfilippo B families. In total, 34 of the 36 mutant alleles were characterized in this study and 20 different mutations were identified including 8 novel changes (R38W, V77G, 407-410del4, 703delT, A246P, Y335C, 1487delT, E639X). The four novel missense mutations were transiently expressed in Chinese hamster ovary cells and all were shown to decrease the NAGLU activity markedly, although A246P did produce 12.7% residual enzyme activity.
Beesley
C E
CE
Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, University College London, London, UK. C.Beesley@ich.ucl.ac.uk
Jackson
M
M
Young
E P
EP
Vellodi
A
A
Winchester
B G
BG
D000118:Acetylglucosaminidase / Q000172:deficiency; D000483:Alleles; D000818:Animals; D016466:CHO Cells; D015331:Cohort Studies; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D005822:Genetic Vectors; D005838:Genotype; D006025:Glycosaminoglycans / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D009084:Mucopolysaccharidosis III / Q000175:diagnosis / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype
D000118:Acetylglucosaminidase; D004247:DNA; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; C033079:alpha-N-acetyl-D-glucosaminidase