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ItemVariants of ST8SIA1 Are Associated with Risk of Developing Multiple SclerosisHusain, S ; Yildirim-Toruner, C ; Rubio, JP ; Field, J ; Schwalb, M ; Cook, S ; Devoto, M ; Vitale, E ; Reitsma, PH (PUBLIC LIBRARY SCIENCE, 2008-07-09)Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system of unknown etiology with both genetic and environmental factors playing a role in susceptibility. To date, the HLA DR15/DQ6 haplotype within the major histocompatibility complex on chromosome 6p, is the strongest genetic risk factor associated with MS susceptibility. Additional alleles of IL7 and IL2 have been identified as risk factors for MS with small effect. Here we present two independent studies supporting an allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12 and encoding ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1. The initial association was made in a single three-generation family where a single-nucleotide polymorphism (SNP) rs4762896, was segregating together with HLA DR15/DQ6 in MS patients. A study of 274 family trios (affected child and both unaffected parents) from Australia validated the association of ST8SIA1 in individuals with MS, showing transmission disequilibrium of the paternal alleles for three additional SNPs, namely rs704219, rs2041906, and rs1558793, with p = 0.001, p = 0.01 and p = 0.01 respectively. These findings implicate ST8SIA1 as a possible novel susceptibility gene for MS.
ItemGenome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20Bahlo, M ; Booth, DR ; Broadley, SA ; Brown, MA ; Foote, SJ ; Griffiths, LR ; Kilpatrick, TJ ; Lechner-Scott, J ; Moscato, P ; Perreau, VM ; Rubio, JP ; Scott, RJ ; Stankovich, J ; Stewart, GJ ; Taylor, BV ; Wiley, J ; Clarke, G ; Cox, MB ; Csurhes, PA ; Danoy, P ; Drysdale, K ; Field, J ; Foote, SJ ; Greer, JM ; Guru, P ; Hadler, J ; McMorran, BJ ; Jensen, CJ ; Johnson, LJ ; McCallum, R ; Merriman, M ; Merriman, T ; Pryce, K ; Tajouri, L ; Wilkins, EJ ; Browning, BL ; Browning, SR ; Perera, D ; Butzkueven, H ; Carroll, WM ; Chapman, C ; Kermode, AG ; Marriott, M ; Mason, D ; Heard, RN ; Pender, MP ; Slee, M ; Tubridy, N ; Willoughby, E (NATURE PUBLISHING GROUP, 2009-07-01)To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).
ItemGas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelinationBinder, MD ; Cate, HS ; Prieto, AL ; Kemper, D ; Butzkueven, H ; Gresle, MM ; Cipriani, T ; Jokubaitis, VG ; Carmeliet, P ; Kilpatrick, TJ (SOC NEUROSCIENCE, 2008-05-14)The TAM family of receptor protein tyrosine kinases comprises three known members, namely Tyro3, Axl, and Mer. These receptors are widely expressed in the nervous system, including by oligodendrocytes, the cell type responsible for myelinating the CNS. We examined the potential role of the TAM family and of their principle cognate ligand, Gas6 (growth arrest gene 6), in modulating the phenotype of the cuprizone model of demyelination. We found that the expression profiles of Axl, Mer, and Gas6 mRNA were increased in the corpus callosum in a temporal profile correlating with the increased migration and proliferation of microglia/macrophages in this model. In contrast, expression of Tyro3 decreased, correlating with the loss of oligodendrocytes. Gas6 both promoted in vitro survival of oligodendrocytes (39.3 +/- 3.1 vs 11.8 +/- 2.4%) and modulated markers of activation in purified cultures of microglia (tumor necrosis factor alpha mRNA expression was reduced approximately 48%). In Gas6-/- mice subjected to cuprizone-challenge, demyelination was greater than in control mice, within the rostral region of the corpus callosum, as assessed by luxol fast blue staining (myelination reduced by 36%) and by ultrastructural analysis. An increased loss of Gst-pi (glutathione S-transferase-pi)-positive oligodendrocytes was also identified throughout the corpus callosum of Gas6-/- mice. Microglial marker expression (ionized calcium-binding adapter molecule 1) was increased in Gas6-/- mice but was restricted to the rostral corpus callosum. Therefore, TAM receptor activation and regulation can independently influence both oligodendrocyte survival and the microglial response after CNS damage.
ItemOligodendrocyte Positioning in Cerebral Cortex is Independent of Projection Neuron LayeringTan, S-S ; Kalloniatis, M ; Truong, H-T ; Binder, MD ; Cate, HS ; Kilpatrick, TJ ; Hammond, VE (WILEY-LISS, 2009-07-01)The factors affecting normal oligodendrocyte positioning in the cerebral cortex are unknown. Apart from the white matter, the highest numbers of oligodendrocytes in the rodent cortex are found in Layers V/VI, where the infragranular neurons normally reside. Few, if any, oligodendrocytes are normally found in the superficial cortical layers. To test whether or not this asymmetric positioning of oligodendrocytes is linked to the lamina positions of Layer V/VI projection neurons, mutant mice that cause neuronal layer inversion were examined. In three lines of mutant mice (Reeler, disabled-1, and p35) examined, representing two different genetic signaling pathways, the oligodendrocyte distribution was altered from an asymmetric to a symmetric distribution pattern. Unlike cortical neurons that are inverted in these mutant mice, the lack of oligodendrocyte inversion suggests a decoupling of the genetic mechanisms governing neuronal versus oligodendrocyte patterning. We conclude that oligodendrocyte positioning is not linked to the layer positions of V/VI projection neurons.