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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: Dystroglycan is a cell membrane receptor that organizes the basement membrane by binding ligands in the extracellular matrix. Proper glycosylation of the α-dystroglycan (α-DG) subunit is essential for these activities, and lack thereof results in neuromuscular disease. Currently, neither the glycan synthesis pathway nor the roles of many known or putative glycosyltransferases that are essential for this process are well understood. Here we show that FKRP, FKTN, TMEM5 and B4GAT1 (formerly known as B3GNT1) localize to the Golgi and contribute to the O-mannosyl post-phosphorylation modification of α-DG. Moreover, we assigned B4GAT1 a function as a xylose β1,4-glucuronyltransferase. Nuclear magnetic resonance studies confirmed that a glucuronic acid β1,4-xylose disaccharide synthesized by B4GAT1 acts as an acceptor primer that can be elongated by LARGE with the ligand-binding heteropolysaccharide. Our findings greatly broaden the understanding of α-DG glycosylation and provide mechanistic insight into why mutations in B4GAT1 disrupt dystroglycan function and cause disease. DOI:
    eLife Sciences 10/2014; 3. DOI:10.7554/eLife.03941 · 9.32 Impact Factor
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    • "The FKTN gene spans 82,989 bp and contains 10 coding exons, the main transcript is 7.4kb encoding a protein of 413 amino acids. Also in this case LGMD2M is a milder form caused by at least one hypomorphic missense mutation in a gene that, with both non-functional alleles, is associated with more severe phenotypes (66): WWS, MEB or congenital muscular dystrophies (67). In LGMD2M the CNS is not affected and the intelligence is normal. "
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    ABSTRACT: Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of muscle disorders, which first affect the voluntary muscles of the hip and shoulder areas. The definition is highly descriptive and less ambiguous by exclusion: non-Xlinked, non-FSH, non-myotonic, non-distal, nonsyndromic, and non-congenital. At present, the genetic classification is becoming too complex, since the acronym LGMD has also been used for a number of other myopathic disorders with overlapping phenotypes. Today, the list of genes to be screened is too large for the gene-by-gene approach and it is well suited for targeted next generation sequencing (NGS) panels that should include any gene that has been so far associated with a clinical picture of LGMD. The present review has the aim of recapitulating the genetic basis of LGMD ordering and of proposing a nomenclature for the orphan forms. This is useful given the pace of new discoveries. Thity-one loci have been identified so far, eight autosomal dominant and 23 autosomal recessive. The dominant forms (LGMD1) are: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin 3), LGMD1D (DNAJB6), LGMD1E (desmin), LGMD1F (transportin 3), LGMD1G (HNRPDL), LGMD1H (chr. 3). The autosomal recessive forms (LGMD2) are: LGMD2A (calpain 3), LGMD2B (dysferlin), LGMD2C (γ sarcoglycan), LGMD2D (α sarcoglycan), LGMD2E (β sarcoglycan), LGMD2F (δ sarcoglycan), LGMD2G (telethonin), LGMD2H (TRIM32), LGMD2I (FKRP), LGMD2J (titin), LGMD2K (POMT1), LGMD2L (anoctamin 5), LGMD2M (fukutin), LGMD2N (POMT2), LGMD2O (POMTnG1), LGMD2P (dystroglycan), LGMD2Q (plectin), LGMD2R (desmin), LGMD2S (TRAPPC11), LGMD2T (GMPPB), LGMD2U (ISPD), LGMD2V (Glucosidase, alpha ), LGMD2W (PINCH2).
    Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases 05/2014; 33(1):1-12.
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    • "The lamina and folia of the cerebellum emerge from the precisely orchestrated proliferation and migration of neurons and the organized growth of neuronal elements including axons and dendrites [1–4]. In light of several devastating malformations of human cerebellar development affecting posture, balance, and motor learning [5–8], the molecular and genetic mechanisms of cerebellar lamination and foliation have been topics of intense investigation. Studies using rodent models have been extremely valuable in the understanding of human cerebellar development and the underlying mechanisms of cerebellar malformations. "
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    ABSTRACT: Molecular layer heterotopia of the cerebellar primary fissure are a characteristic of many rat strains and are hypothesized to result from defect of granule cells exiting the external granule cell layer during cerebellar development. However, the cellular and axonal constituents of these malformations remain poorly understood. In the present report, we use histochemistry and immunocytochemistry to identify neuronal, glial, and axonal classes in molecular layer heterotopia. In particular, we identify parvalbumin-expressing molecular layer interneurons in heterotopia as well as three glial cell types including Bergmann glia, Olig2-expressing oligodendrocytes, and Iba1-expressing microglia. In addition, we document the presence of myelinated, serotonergic, catecholaminergic, and cholinergic axons in heterotopia indicating possible spinal and brainstem afferent projections to heterotopic cells. These findings are relevant toward understanding the mechanisms of normal and abnormal cerebellar development.
    09/2013; 2013:805467. DOI:10.1155/2013/805467
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