Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 335 (6064): 93-96

Copyright © 2012 by the American Association for the Advancement of Science

Dystroglycan Function Requires Xylosyl- and Glucuronyltransferase Activities of LARGE

Kei-ichiro Inamori,1,* Takako Yoshida-Moriguchi,1,* Yuji Hara,1 Mary E. Anderson,1 Liping Yu,2 Kevin P. Campbell1,{dagger}

Abstract: Posttranslational modification of alpha-dystroglycan (α-DG) by the like-acetylglucosaminyltransferase (LARGE) is required for it to function as an extracellular matrix (ECM) receptor. Mutations in the LARGE gene have been identified in congenital muscular dystrophy patients with brain abnormalities. However, the precise function of LARGE remains unclear. Here we found that LARGE could act as a bifunctional glycosyltransferase, with both xylosyltransferase and glucuronyltransferase activities, which produced repeating units of [–3-xylose–α1,3-glucuronic acid-β1–]. This modification allowed α-DG to bind laminin-G domain–containing ECM ligands.

1 Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, 4283 Carver Biomedical Research Building, 285 Newton Road, Iowa City, IA 52242–1101, USA.
2 Medical Nuclear Magnetic Resonance Facility, University of Iowa Roy J. and Lucille A. Carver College of Medicine, B291 Carver Biomedical Research Building, 285 Newton Road, Iowa City, IA 52242–1101, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: kevin-campbell{at}

The transgenic expression of LARGE exacerbates the muscle phenotype of dystroglycanopathy mice.
C. Whitmore, M. Fernandez-Fuente, H. Booler, C. Parr, M. Kavishwar, A. Ashraf, E. Lacey, J. Kim, R. Terry, M. R. Ackroyd, et al. (2014)
Hum. Mol. Genet. 23, 1842-1855
   Abstract »    Full Text »    PDF »
POMK mutation in a family with congenital muscular dystrophy with merosin deficiency, hypomyelination, mild hearing deficit and intellectual disability.
A. von Renesse, M. V. Petkova, S. Lutzkendorf, J. Heinemeyer, E. Gill, C. Hubner, A. von Moers, W. Stenzel, and M. Schuelke (2014)
J. Med. Genet. 51, 275-282
   Abstract »    Full Text »    PDF »
O-mannosylation of cadherins.
J. U. Baenziger (2013)
PNAS 110, 20858-20859
   Full Text »    PDF »
HNK-1 sulfotransferase-dependent sulfation regulating laminin-binding glycans occurs in the post-phosphoryl moiety on {alpha}-dystroglycan.
N. Nakagawa, H. Takematsu, and S. Oka (2013)
Glycobiology 23, 1066-1074
   Abstract »    Full Text »    PDF »
SGK196 Is a Glycosylation-Specific O-Mannose Kinase Required for Dystroglycan Function.
T. Yoshida-Moriguchi, T. Willer, M. E. Anderson, D. Venzke, T. Whyte, F. Muntoni, H. Lee, S. F. Nelson, L. Yu, and K. P. Campbell (2013)
Science 341, 896-899
   Abstract »    Full Text »    PDF »
Impaired viability of muscle precursor cells in muscular dystrophy with glycosylation defects and amelioration of its severe phenotype by limited gene expression.
M. Kanagawa, C.-C. Yu, C. Ito, S.-i. Fukada, M. Hozoji-Inada, T. Chiyo, A. Kuga, M. Matsuo, K. Sato, M. Yamaguchi, et al. (2013)
Hum. Mol. Genet. 22, 3003-3015
   Abstract »    Full Text »    PDF »
Loss of Branched O-Mannosyl Glycans in Astrocytes Accelerates Remyelination.
K. Kanekiyo, K.-i. Inamori, S. Kitazume, K. Sato, J. Maeda, M. Higuchi, Y. Kizuka, H. Korekane, I. Matsuo, K. Honke, et al. (2013)
J. Neurosci. 33, 10037-10047
   Abstract »    Full Text »    PDF »
Missense mutations in {beta}-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome.
K. Buysse, M. Riemersma, G. Powell, J. van Reeuwijk, D. Chitayat, T. Roscioli, E.-J. Kamsteeg, C. van den Elzen, E. van Beusekom, S. Blaser, et al. (2013)
Hum. Mol. Genet. 22, 1746-1754
   Abstract »    Full Text »    PDF »
Deciphering the Glycosylome of Dystroglycanopathies Using Haploid Screens for Lassa Virus Entry.
L. T. Jae, M. Raaben, M. Riemersma, E. van Beusekom, V. A. Blomen, A. Velds, R. M. Kerkhoven, J. E. Carette, H. Topaloglu, P. Meinecke, et al. (2013)
Science 340, 479-483
   Abstract »    Full Text »    PDF »
The O-Mannosylation Pathway: Glycosyltransferases and Proteins Implicated in Congenital Muscular Dystrophy.
L. Wells (2013)
J. Biol. Chem. 288, 6930-6935
   Abstract »    Full Text »    PDF »
Understanding Human Glycosylation Disorders: Biochemistry Leads the Charge.
H. H. Freeze (2013)
J. Biol. Chem. 288, 6936-6945
   Abstract »    Full Text »    PDF »
LARGE2 generates the same xylose- and glucuronic acid-containing glycan structures as LARGE.
A. Ashikov, F. F. Buettner, B. Tiemann, R. Gerardy-Schahn, and H. Bakker (2013)
Glycobiology 23, 303-309
   Abstract »    Full Text »    PDF »
Xylosyl- and glucuronyltransferase functions of LARGE in {alpha}-dystroglycan modification are conserved in LARGE2.
K.-i. Inamori, Y. Hara, T. Willer, M. E. Anderson, Z. Zhu, T. Yoshida-Moriguchi, and K. P. Campbell (2013)
Glycobiology 23, 295-302
   Abstract »    Full Text »    PDF »
Loss of LARGE2 Disrupts Functional Glycosylation of {alpha}-Dystroglycan in Prostate Cancer.
A. K. Esser, M. R. Miller, Q. Huang, M. M. Meier, D. Beltran-Valero de Bernabe, C. S. Stipp, K. P. Campbell, C. F. Lynch, B. J. Smith, M. B. Cohen, et al. (2013)
J. Biol. Chem. 288, 2132-2142
   Abstract »    Full Text »    PDF »
ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies.
S. Cirak, A. R. Foley, R. Herrmann, T. Willer, S. Yau, E. Stevens, S. Torelli, L. Brodd, A. Kamynina, P. Vondracek, et al. (2013)
   Abstract »    Full Text »    PDF »
O-Mannose and O-N-acetyl galactosamine glycosylation of mammalian {alpha}-dystroglycan is conserved in a region-specific manner.
A. Gomez Toledo, M. Raducu, J. Cruces, J. Nilsson, A. Halim, G. Larson, U. Ruetschi, and A. Grahn (2012)
Glycobiology 22, 1413-1423
   Abstract »    Full Text »    PDF »
Human Natural Killer-1 Sulfotransferase (HNK-1ST)-induced Sulfate Transfer Regulates Laminin-binding Glycans on {alpha}-Dystroglycan.
N. Nakagawa, H. Manya, T. Toda, T. Endo, and S. Oka (2012)
J. Biol. Chem. 287, 30823-30832
   Abstract »    Full Text »    PDF »
Developmental Expression of the Neuron-specific N-Acetylglucosaminyltransferase Vb (GnT-Vb/IX) and Identification of Its in Vivo Glycan Products in Comparison with Those of Its Paralog, GnT-V.
J. K. Lee, R. T. Matthews, J.-M. Lim, K. Swanier, L. Wells, and J. M. Pierce (2012)
J. Biol. Chem. 287, 28526-28536
   Abstract »    Full Text »    PDF »
Absence of Post-phosphoryl Modification in Dystroglycanopathy Mouse Models and Wild-type Tissues Expressing Non-laminin Binding Form of {alpha}-Dystroglycan.
A. Kuga, M. Kanagawa, A. Sudo, Y. M. Chan, M. Tajiri, H. Manya, Y. Kikkawa, M. Nomizu, K. Kobayashi, T. Endo, et al. (2012)
J. Biol. Chem. 287, 9560-9567
   Abstract »    Full Text »    PDF »
Mislocalization of Fukutin Protein by Disease-causing Missense Mutations Can Be Rescued with Treatments Directed at Folding Amelioration.
M. Tachikawa, M. Kanagawa, C.-C. Yu, K. Kobayashi, and T. Toda (2012)
J. Biol. Chem. 287, 8398-8406
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882