Identification of 12 novel mutations in the alpha-N-acetylglucosaminidase gene in 14 patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB).

Abstract

Sanfilippo syndrome type B or mucopolysaccharidosis type IIIB (MPS IIIB) is one of a group of lysosomal storage disorders that are characterised by the inability to breakdown heparan sulphate. In MPS IIIB, there is a deficiency in the enzyme a-N-acetylglucosaminidase (NAGLU) and early clinical symptoms include aggressive behaviour and hyperactivity followed by progressive mental retardation. The disease is autosomal recessive and the gene for NAGLU, which is situated on chromosome 17q21, is approximately 8.5 kb in length and contains six exons. Primers were designed to amplify the entire coding region and intron/exon boundaries of the NAGLU gene in 10 fragments. The PCR products were analysed for sequence changes using SSCP analysis and fluorescent DNA sequencing technology. Sixteen different putative mutations were detected in DNA from 14 MPS IIIB patients, 12 of which have not been found previously. The mutations include four deletions (219-237de119, 334-358del25, 1335delC, 2099delA), two insertions (1447( -1448insT, 1932, two nonsense mutations (R297X, R626X), and eight missense mutations (F48C, Y140C, R234C, W268R, P521L, R565W, L591P, E705K). In this study, the Y140C, R297X, and R626X mutations were all found in more than one patient and together accounted for 25% of mutant alleles. (7Med Genet 1998;35:910-914)

Prevalence and Novel Mutations of Lysosomal Storage Disorders in United Arab Emirates

“…The amino acid substitution (p.R565L) involved a highly conserved residue, Table 2. Other mutations affecting the same amino acid were previously shown to cause MPS IIIB (Beesley et al 1998;Bunge et al 1999;Weber et al 1999). The two siblings with Batten disease had homozygous (novel) deletions involving exon 3, introns 6 and 8, and exons 11, 14, and 15 of the CLN3 gene (Table 2).…”

Structural and mechanistic insight into the basis of mucopolysaccharidosis IIIB

“…org), is responsible for cleaving the glycosidic bond found in the backbone of heparan and thus plays a key role in heparan recycling. More than 100 different mutations in the naglu gene have been associated with the MPS IIIB phenotype, and biochemical studies have confirmed the deleterious effects of many of these mutations (1)(2)(3)(4)(5)(6)(7)(8)(9). Despite having been cloned Ͼ10 years ago, no structural or mechanistic data for NAGLU have been obtained, hindering the development of potential therapeutic strategies to treat patients suffering from MPS IIIB.…”

Sanfilippo type B syndrome: five patients with an R565P homozygous mutation in the α-N-acetylglucosaminidase gene from the Okinawa islands in Japan

“…Two siblings with an attenuated phenotype were compound heterozygous for R565P/F314L, and one patient with a severe phenotype was homozygous for R565P. To our knowledge, excluding Tanaka's report, 88 different mutations have been reported in 116 MPS IIIB patients, and 39 patients showed homozygous mutations Schmidtchen et al 1998;Beesley et al 1998;Bunge et al 1999;Weber et al 1999;Tessitore et al 2000). In previous reports, no apparent common mutations were identified.…”

“…Since little is known about the catalytic site and tertiary structure of the enzyme, it is very difficult to draw any conclusions on the effect of the missense mutation on enzyme function. However, two other missense mutations at Arg-565 (R565W and R565Q) have been reported in MPS IIIB patients with a severe phenotype (Beesley et al 1998;Bunge et al 1999;Weber et al 1999;Tanaka et al 2002). Arginine is positively charged and more hydrophilic than proline, which is uncharged and moderately polar (Nelson and Cox 2000).…”