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LARGE Expression in Different Types of Muscular Dystrophies Other Than Dystroglycanopathy Burcu Balci-Hayta1*, Beril Talim2, Gulsev Kale2 and Pervin Dincer1

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LARGE Expression in Different Types of Muscular Dystrophies Other Than Dystroglycanopathy Burcu Balci-Hayta1*, Beril Talim2, Gulsev Kale2 and Pervin Dincer1 Balci-Hayta et al. BMC Neurology (2018) 18:207 https://doi.org/10.1186/s12883-018-1207-0 RESEARCHARTICLE Open Access LARGE expression in different types of muscular dystrophies other than dystroglycanopathy Burcu Balci-Hayta1*, Beril Talim2, Gulsev Kale2 and Pervin Dincer1 Abstract Background: Alpha-dystroglycan (αDG) is an extracellular peripheral glycoprotein that acts as a receptor for both extracellular matrix proteins containing laminin globular domains and certain arenaviruses. An important enzyme, known as Like-acetylglucosaminyltransferase (LARGE), has been shown to transfer repeating units of -glucuronic acid-β1,3-xylose-α1,3- (matriglycan) to αDG that is required for functional receptor as an extracellular matrix protein scaffold. The reduction in the amount of LARGE-dependent matriglycan result in heterogeneous forms of dystroglycanopathy that is associated with hypoglycosylation of αDG and a consequent lack of ligand-binding activity. Our aim was to investigate whether LARGE expression showed correlation with glycosylation of αDG and histopathological parameters in different types of muscular dystrophies, except for dystroglycanopathies. Methods: The expression level of LARGE and glycosylation status of αDG were examined in skeletal muscle biopsies from 26 patients with various forms of muscular dystrophy [Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), sarcoglycanopathy, dysferlinopathy, calpainopathy, and merosin and collagen VI deficient congenital muscular dystrophies (CMDs)] and correlation of results with different histopathological features was investigated. Results: Despite the fact that these diseases are not caused by defects of glycosyltransferases, decreased expression of LARGE was detected in many patient samples, partly correlating with the type of muscular dystrophy. Although immunolabelling of fully glycosylated αDG with VIA4–1 was reduced in dystrophinopathy patients, no significant relationship between reduction of LARGE expression and αDG hypoglycosylation was detected. Also, Merosin deficient CMD patients showed normal immunostaining with αDG despite severe reduction of LARGE expression. Conclusions: Our data shows that it is not always possible to correlate LARGE expression and αDG glycosylation in different types of muscular dystrophies and suggests that there might be differences in αDG processing by LARGE which could be regulated under different pathological conditions. Keywords: LARGE, Alpha-dystroglycan, Hypoglycosylation, Muscular dystrophy, Skeletal muscle Background synthesized as a precursor molecule that is post-translation- Dystroglycan (DG), a heterodimeric transmembrane ally cleaved into a cell surface α- and a transmembrane β- glycoprotein, is a central component of the dystrophin- subunits [2]. The extracellular subunit, alpha-dystroglycan glycoprotein complex (DGC) and responsible for a (αDG), is a highly glycosylated basement membrane protein variety of physiological and developmental processes, that acts as a receptor for non-collagenous proteins in the including muscle stabilization, basement membrane extracellular matrix (ECM) containing laminin globular do- assembly, cell migration and signalling [1]. The protein is mains, and for Old World arenaviruses [1, 3–5]. Mutations in the DG-encoding gene (DAG1) [6, 7]andseveralother genes whose products are involved, directly or indirectly, in * Correspondence: [email protected] α 1Department of Medical Biology, Hacettepe University Faculty of Medicine, glycosylation pathway of DG [8]havebeenidentifiedin 06100 Sihhiye, Ankara, Turkey Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Balci-Hayta et al. BMC Neurology (2018) 18:207 Page 2 of 8 various forms of congenital and limb-girdle muscular dys- different types of muscular dystrophies, except for trophies (CMD/ LGMDs). These disorders are all associ- dystroglycanopathies [i.e. Duchenne muscular dystrophy ated with hypoglycosylation of αDG and a consequent lack (DMD), Becker muscular dystrophy (BMD), sarcoglyca- of ligand-binding activity and thus are collectively termed nopathy, dysferlinopathy, calpainopathy, and merosin as dystroglycanopathies [9]. and collagen VI deficient CMDs]. Correlation between Although the precise glycosylation pathway of αDG different histopathological features, LARGE expression is not fully understood, the function of Like-acetylglu- profile and glycosylation status of αDG was investigated. cosaminyltransferase (LARGE) enzyme has been of We detected reduced expression level of LARGE in particular interest. It is encoded by one of the largest different types of muscular dystrophies, partly correlat- genes (LARGE) in the human genome [10–12], which is ing with the severity of dystrophic changes, but we did mutated in the myodystrophy mouse (LARGE-myd) [10, not find any significant relationship between reduction 13] and in patients affected by MDC1D, a subclass of of LARGE expression and VIA4–1 immunoreactivity. CMD associated with skeletal muscle and structural brain involvement [11]. The mentioned enzyme is a bifunctional Methods glycosyltransferase, with both xylosyltransferase and glu- Patients and muscle biopsies curonyltransferase activities and plays an important role The study protocol was approved by the Hacettepe in the glycosylation pathway of αDG. It transfers a novel University Faculty of Medicine Ethical Review Board heteropolysaccharide structure, repeating units of -glucur- (FON 10/35–11). As the legal age of consent is 18 years onic acid-β1,3-xylose-α1,3- to the basement membrane of age in Turkey, written informed consent was obtained receptor DG [14]. This structure has been recently termed from patients’ parents or legal guardians at the time of as matriglycan, which is bound to the αDG through a diagnostic muscle biopsy. Skeletal muscle biopsies from phosphorylated O-mannosyl glycan anchored at Thr317 3 controls and 26 patients with clinicopathological and/ and Thr319 in the mucin-like domain [8, 15, 16]. It is or molecular diagnosis of various forms of muscular dys- required for the αDG to bind laminin-G domain- trophy other than dystroglycanopathy were included in containing ECM ligands including laminin, agrin, perlecan this study. The number of patients in each disease type and neurexin [4, 17–19]. It has been reported that is indicated in parentheses; DMD (3), BMD (4), sarcogly- LARGE-dependent matriglycan structure plays an import- canopathy (5), dysferlinopathy (1), calpainopathy (1), ant role for normal skeletal muscle function and the con- Merosin deficient CMD (4), Collagen VI deficient CMD sequent reduction in the amount of glycans on αDG (3), unclassified CMD (2), and unclassified MD (3). All causes structural alterations of the basement membrane, patients have been investigated in the Department of immature neuromuscular junctions and dysfunctional Pediatrics at Hacettepe University Faculty of Medicine muscle predisposed to dystrophy [20]. Uniquely, transient and open biopsies were taken from vastus lateralis overexpression of LARGE has been shown to increase gly- muscle at the time of diagnosis. The muscle biopsy spec- cosylation of αDG as evaluated by increased immunoreac- imens were rapidly frozen in isopentane cooled in liquid tivity to antibodies IIH6 and VIA4–1 both of which are nitrogen and kept at − 80 °C until use. Serial transverse known to recognize carbohydrate moieties and leads to a muscle sections were cut by cryostat for histochemical recovery of receptor function in cells derived from staining. Standard histological and histochemical tech- patients diagnosed as Fukuyama CMD (FCMD), niques were applied to cryostat sections, including muscle-eye-brain disease (MEB) and Walker–Warburg Haematoxylin and eosin (H&E), modified Gomori syndrome (WWS) [17]. Also, the identical results has been trichrome, periodic acid Schiff, oil-red-O, nicotinamide reported in vivo, after adenovirus or adeno-associated adenine dinucleotide dehydrogenase-tetrazolium reduc- virus mediated gene transfer of LARGE in Fukutin (FKTN), tase, succinic dehydrogenase, cytochrome-c oxidase and Fukutin-related protein (FKRP) and Protein-O-mannose ATPase. Immunohistochemical and/or immunofluores- ß2-N-acetylglucosaminyltransferase 1 (POMGNT1) defi- cent studies were done at the time of diagnosis, using cient mice models [21–23]. Although a recent study dem- antibodies against dystrophins, sarcoglycans, dysferlin, lam- onstrates that fukutin is required for the ability of LARGE inin α2 (merosin), collagen VI, and αDG, as appropriate. to hyperglycosylate αDG [24], this strategy is already regarded as a promising therapeutic approach for prevent- ing/slowing progression of a broad range of dystroglycano- Histopathological evaluation pathies regardless of the causative gene defects. However, it H&E stained archive sections were examined to identify remains crucial to analyze such a strategy in different
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