Multiple sclerosis (MS), an inflammatory autoimmune demyelinating disorder of the central nervous system, is the most common cause of acquired neurological dysfunction arising in the second to fourth decades of life. A genetic component to MS is indicated by an increased relative risk of 20-40 to siblings compared to the general population (lambda s), and an increased concordance rate in monozygotic compared to dizygotic twins. Association and/or linkage studies to candidate genes have produced many reports of significant genetic effects including those for the major histocompatability complex (MHC; particularly the HLA-DR2 allele), immunoglobulin heavy chain (IgH), T-cell receptor (TCR) and myelin basic protein (MBP) loci. With the exception of the MHC, however, these results have been difficult to replicate and/or apply beyond isolated populations. We have therefore conducted a two-stage, multi-analytical genomic screen to identify genomic regions potentially harbouring MS susceptibility genes. We genotyped 443 markers and 19 such regions were identified. These included the MHC region on 6p, the only region with a consistently reported genetic effect. However, no single locus generated overwhelming evidence of linkage. Our results suggest that a multifactorial aetiology, including both environmental and multiple genetic factors of moderate effect, is more likely than an aetiology consisting of simple mendelian disease gene(s).

A highly efficient chemoenzymatic synthesis of N-glycopeptides was achieved. It was found that using synthetic oligosaccharide oxazolines, the mimics of the presumed oxazolinium ion intermediate formed in a retaining mechanism of substrate-assisted catalysis, as the donor substrates and GlcNAc-peptides as the acceptors, the endo-beta-N-acetylglucosaminidase (ENGase)-catalyzed transglycosylation gave a high yield (73-82%) of the corresponding glycopeptides in a regio- and stereospecific manner, regardless of the size of the peptide portions. The use of the oligosaccharide oxazolines as donor substrates not only expanded the substrate availability but also led to a substantial enhancement of the synthetic efficiency, compared to the use of natural N-glycans.

[reaction: see text] A highly efficient endoglycosidase-catalyzed synthesis of homogeneous glycoproteins is described. By using ribonuclease B as a model system, it was demonstrated that Endo-A could efficiently attach a preassembled oligosaccharide to a GlcNAc-containing protein in a regio- and stereospecific manner, when the corresponding sugar oxazoline was used as the donor substrate. The method allows the synthesis of both natural and tailor-made N-linked glycoproteins in excellent yield.