GENOTYPE-PHENOTYPE CORRESPONDENCE IN SANFILIPPO SYNDROME TYPE-B

Sanfilippo syndrome type B, or mucopolysaccharidosis type IIIB, result s from defects in the gene for alpha-N-acetylglucosaminidase (NAGLU); only a few mutations have been described. To rapidly identify most NAG LU mutations, an automated sequencing procedure was developed for anal ysis of the entire coding region, including exon-intron borders. By th is method, eight affected families were studied, and the mutations in all 16 alleles were identified, more than doubling the number of publi shed mutations for this gene. Eight mutations were described for the f irst time: five missense mutations (Y140C, Y455C, P521L, SG12G, and R6 74C), two nonsense mutations (W675X and Q706X), and one 24-nucleotide insertion. Currently, 36% of all point mutations (8 of 22 alleles) inv olve R674, a codon having a CpG dinucleotide in the critical initial p osition. Other mutations were found in more than one family, raising t he possibility that some may be relatively common and, possibly, ancie nt mutations. Six new nonpathological mutations were also identified a nd likely represent polymorphic variants of the NAGLU gene, two of whi ch might alter enzyme level. Establishing genotype-phenotype relations hips will be vital in the evaluation of experimental treatments such a s gene therapy.