NAGLU Mutations Underlying Sanfilippo Syndrome Type B

Abstract

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.

Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes

“…3 Another possible explanation is that the DNA structure leaves this area more vulnerable to mutagenic events than other parts of the gene. A suggested 16 crucial role of the carboxy end of the protein in enzyme structure/function cannot necessarily be assumed.…”

“…3,10,15,16 We now report the analysis of the NAGLU alleles of 40 MPS IIIB patients revealing strong heterogeneity with 25 novel mutations and two polymorphisms identified, including one mutation (R643C) common amongst Dutch patients that is clearly associated with the attenuated form of the disease.…”

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.…”