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    • "Our previous work showed that the ER-resident enzymes POMGNT2 (GTDC2), B3GALNT2 and POMK (SGK196) contribute to synthesis of the phosphorylated Core M3 trisaccharide on α-DG, a moiety that is required as platform for further modification with the LARGE mediated laminin-binding glycan (Yoshida-Moriguchi et al., 2013). However, a number of additional genes, namely FKTN (Fukutin) (Kobayashi et al., 1998; de Bernabe et al., 2003), FKRP (Fukutin-related protein) (Brockington et al., 2001; Beltran-Valero de Bernabe et al., 2004) TMEM5 (Vuillaumier-Barrot et al., 2012) and B4GAT1 (B3GNT1) (Wright et al., 2012; Buysse et al., 2013; Shaheen et al., 2013) are known to be crucial for proper α-DG glycosylation, yet how they contribute has not yet been determined (Figure 1— figure supplement 1). To investigate if these unassigned genes are involved in the pre-or postphosphorylation process of Core M3, we expressed Fc-tagged recombinant α-DG (DGFc340) in [ 32 P] orthophosphate-labeled control and glycosylation-deficient cells. "
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    ABSTRACT: eLife digest Dystroglycan is a protein that is critical for the proper function of many tissues, especially muscles and brain. Dystroglycan helps to connect the structural network inside the cell with the matrix outside of the cell. The extracellular matrix fills the space between the cells to serve as a scaffold and hold cells together within a tissue. It is well established that the interaction of cells with their extracellular environments is important for structuring tissues, as well as for helping cells to specialize and migrate. These interactions also play a role in the progression of cancer. As is the case for many proteins, dystroglycan must be modified with particular sugar molecules in order to work correctly. Enzymes called glycosyltransferases are responsible for sequentially assembling a complex array of sugar molecules on dystroglycan. This modification is essential for making dystroglycan ‘sticky’, so it can bind to the components of the extracellular matrix. If sugar molecules are added incorrectly, dystroglycan loses its ability to bind to these components. This causes congenital muscular dystrophies, a group of diseases that are characterized by a progressive loss of muscle function. Willer et al. use a wide range of experimental techniques to investigate the types of sugar molecules added to dystroglycan, the overall structure of the resulting ‘sticky’ complex and the mechanism whereby it is built. This reveals that a glycosyltransferase known as B3GNT1 is one of the enzymes responsible for adding a sugar molecule to the complex. This enzyme was first described in the literature over a decade ago, and the name B3GNT1 was assigned, according to a code, to reflect the sugar molecule it was thought to transfer to proteins. However, Willer et al. (and independently, Praissman et al.) find that this enzyme actually attaches a different sugar modification to dystroglycan, and so should therefore be called B4GAT1 instead. Willer et al. find that the sugar molecule added by the B4GAT1 enzyme acts as a platform for the assembly of a much larger sugar polymer that cells use to anchor themselves within a tissue. Some viruses–including Lassa virus, which causes severe fever and bleeding–also use the ‘sticky’ sugar modification of dystroglycan to bind to and invade cells, causing disease in humans. Understanding the structure of this complex, and how these sugar modifications are added to dystroglycan, could therefore help to develop treatments for a wide range of diseases like progressive muscle weakening and viral infections. DOI:
    eLife Sciences 10/2014; 3. DOI:10.7554/eLife.03941 · 8.52 Impact Factor
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    • "Dentate gyrus abnormalities in POMGnT1 knockout [12], POMT2 knockout [18], and Large myd mice [14] include a wavy morphology of the inferior blade (endal blade). In this study, we showed that this dysmorphology is composed of disruptions of the pial basement membrane and ectopia of dentate gyrus. "
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    ABSTRACT: A subset of congenital muscular dystrophies (CMDs) has central nervous system manifestations. There are good mouse models for these CMDs that include POMGnT1 knockout, POMT2 knockout and Large(myd) mice with all exhibiting defects in dentate gyrus. It is not known how the abnormal dentate gyrus is formed during the development. In this study, we conducted a detailed morphological examination of the dentate gyrus in adult and newborn POMGnT1 knockout, POMT2 knockout, and Large(myd) mice by immunofluorescence staining and electron microscopic analyses. We observed that the pial basement membrane overlying the dentate gyrus was disrupted and there was ectopia of granule cell precursors through the breached pial basement membrane. Besides these, the knockout dentate gyrus exhibited reactive gliosis in these mouse models. Thus, breaches in the pial basement membrane are associated with defective dentate gyrus development in mouse models of congenital muscular dystrophies.
    Neuroscience Letters 11/2011; 505(1):19-24. DOI:10.1016/j.neulet.2011.09.040 · 2.06 Impact Factor
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    • "A 3 kb retrotransposon insertion mutation in the 3 0 -untranslated region of this gene, descended from a single ancestor, is responsible for the relatively high prevalence of the disorder in Japan [4]. Among the first cases of FKTN-dystroglycanopathy reported outside of Japan are two Turkish patients, both with homozygous null mutations, who suffered from a severe, WWS-like phenotype with early lethality [5] [6]. "
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    ABSTRACT: The dystroglycanopathies comprise a clinically and genetically heterogeneous group of muscular dystrophies characterized by deficient glycosylation of alpha-dystroglycan. Mutations in the fukutin (FKTN) gene have primarily been identified among patients with classic Fukuyama congenital muscular dystrophy (FCMD), a severe form of dystroglycanopathy characterized by CMD, cobblestone lissencephaly and ocular defects. We describe two brothers of Caucasian and Japanese ancestry with normal intelligence and limb-girdle muscular dystrophy (LGMD) due to compound heterozygous FKTN mutations. Muscle biopsy showed a dystrophy with selectively reduced alpha-dystroglycan glycoepitope immunostaining. Immunoblots revealed hypoglycosylation of alpha-dystroglycan and loss of laminin binding. FKTN gene sequencing identified two variants: c.340G>A and c.527T>C, predicting missense mutations p.A114T and p.F176S, respectively. Our results provide further evidence for ethnic and allelic heterogeneity and the presence of milder phenotypes in FKTN-dystroglycanopathy despite a substantial degree of alpha-dystroglycan hypoglycosylation in skeletal muscle.
    Neuromuscular Disorders 03/2009; 19(5):352-6. DOI:10.1016/j.nmd.2009.03.001 · 3.13 Impact Factor
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