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Fukutin and Fukutin-Related Protein (FKRP)

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Handbook of Glycosyltransferases and Related Genes

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Abstract

Abnormal glycosylation of proteins is often associated with human diseases. A group of muscular dystrophy, dystroglycanopathy, is caused by abnormal glycosylation of dystroglycan (DG), a cell-surface laminin receptor. Fukutin (gene symbol, FKTN) and fukutin-related protein (FKRP; gene symbol, FKRP) are putative glycosyltransferases involved in the synthesis of a unique glycan structure of α-DG (Fig. 105.1), which is required for laminin-binding activity. Both genes were originally identified as causative genes of muscular dystrophies: FKTN for Fukuyama congenital muscular dystrophy (FCMD) and FKRP for congenital muscular dystrophy 1C (MDC1C) and limb-girdle type 2I (LGMD2I). Mutations in FKTN or FKRP lead to abnormal glycosylation and subsequent reduction of the ligand-binding activity of α-DG, which is associated with the pathology of the skeletal muscle, cardiac muscle, and the central nervous system. Consistently, studies using genetically modified animals support that fukutin/FKRP-dependent modification plays biologically important roles such as the maintenance of muscle cell membrane integrity, cortical histogenesis, and normal ocular development.

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References

  • Ackroyd MR, Skordis L, Kaluarachchi M, Godwin J, Prior S, Fidanboylu M, Piercy RJ, Muntoni F, Brown SC (2009) Reduced expression of fukutin related protein in mice results in a model for fukutin related protein associated muscular dystrophies. Brain 132:439–451

    Article  CAS  PubMed  Google Scholar 

  • Aravind L, Koonin EV (1999) The fukutin protein family – predicted enzymes modifying cell-surface molecules. Curr Biol 9:R836–R837

    Article  CAS  PubMed  Google Scholar 

  • Barresi R, Campbell KP (2006) Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci 119:199–207

    Article  CAS  PubMed  Google Scholar 

  • Beedle AM, Nienaber PM, Campbell KP (2007) Fukutin-related protein associates with the sarcolemmal dystrophin-glycoprotein complex. J Biol Chem 282:16713–16717

    Article  CAS  PubMed  Google Scholar 

  • Beedle AM, Turner AJ, Saito Y, Lueck JD, Foltz SJ, Fortunato MJ, Nienaber PM, Campbell KP (2012) Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy. J Clin Invest 122:3330–3342

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Breton C, Imberty A (1999) Structure/function studies of glycosyltransferases. Curr Opin Struct Biol 9:563–571

    Article  CAS  PubMed  Google Scholar 

  • Brockington M, Yuva Y, Prandini P, Brown SC, Torelli S, Benson MA, Herrmann R, Anderson LV, Bashir R, Burgunder JM, Fallet S, Romero N, Fardeau M, Straub V, Storey G, Pollitt C, Richard I, Sewry CA, Bushby K, Voit T, Blake DJ, Muntoni F (2001a) Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet 10:2851–2859

    Article  CAS  PubMed  Google Scholar 

  • Brockington M, Blake DJ, Prandini P, Brown SC, Torelli S, Benson MA, Ponting CP, Estournet B, Romero NB, Mercuri E, Voit T, Sewry CA, Guicheney P, Muntoni F (2001b) Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet 69:1198–1209

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chan YM, Keramaris-Vrantsis E, Lidov HG, Norton JH, Zinchenko N, Gruber HE, Thresher R, Blake DJ, Ashar J, Rosenfeld J, Lu QL (2010) Fukutin-related protein is essential for mouse muscle, brain and eye development and mutation recapitulates the wide clinical spectrums of dystroglycanopathies. Hum Mol Genet 19:3995–4006

    Article  CAS  PubMed  Google Scholar 

  • Chiba A, Matsumura K, Yamada H, Inazu T, Shimizu T, Kusunoki S, Kanazawa I, Kobata A, Endo T (1997) Structures of sialylated O-linked oligosaccharides of bovine peripheral nerve alpha-dystroglycan. The role of a novel O-mannosyl-type oligosaccharide in the binding of alpha-dystroglycan with laminin. J Biol Chem 272:2156–2162

    Article  CAS  PubMed  Google Scholar 

  • Chiyonobu T, Sasaki J, Nagai Y, Takeda S, Funakoshi H, Nakamura T, Sugimoto T, Toda T (2005) Effects of fukutin deficiency in the developing mouse brain. Neuromuscul Disord 15:416–426

    Article  PubMed  Google Scholar 

  • Dolatshad NF, Brockington M, Torelli S, Skordis L, Wever U, Wells DJ, Muntoni F, Brown SC (2005) Mutated fukutin-related protein (FKRP) localises as wild type in differentiated muscle cells. Exp Cell Res 309:370–378

    Article  CAS  PubMed  Google Scholar 

  • Esapa CT, Benson MA, Schröder JE, Martin-Rendon E, Brockington M, Brown SC, Muntoni F, Kröger S, Blake DJ (2002) Functional requirements for fukutin-related protein in the Golgi apparatus. Hum Mol Genet 11:3319–3331

    Article  CAS  PubMed  Google Scholar 

  • Fukuyama Y, Osawa M, Suzuki H (1981) Congenital progressive muscular dystrophy of the Fukuyama type – clinical, genetic and pathological considerations. Brain Dev 3:1–29

    Article  CAS  PubMed  Google Scholar 

  • Godfrey C, Clement E, Mein R, Brockington M, Smith J, Talim B, Straub V, Robb S, Quinlivan R, Feng L, Jimenez-Mallebrera C, Mercuri E, Manzur AY, Kinali M, Torelli S, Brown SC, Sewry CA, Bushby K, Topaloglu H, North K, Abbs S, Muntoni F (2007) Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 130:2725–2735

    Article  PubMed  Google Scholar 

  • Godfrey C, Foley AR, Clement E, Muntoni F (2011) Dystroglycanopathies: coming into focus. Curr Opin Genet Dev 21:278–285

    Article  CAS  PubMed  Google Scholar 

  • Hara Y, Balci-Hayta B, Yoshida-Moriguchi T, Kanagawa M, Beltrán-Valero de Bernabé D, Gündeşli H, Willer T, Satz JS, Crawford RW, Burden SJ, Kunz S, Oldstone MB, Accardi A, Talim B, Muntoni F, Topaloğlu H, Dinçer P, Campbell KP (2011) A dystroglycan mutation associated with limb-girdle muscular dystrophy. N Engl J Med 364:939–946

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hayashi YK, Ogawa M, Tagawa K, Noguchi S, Ishihara T, Nonaka I, Arahata K (2001) Selective deficiency of alpha-dystroglycan in Fukuyama-type congenital muscular dystrophy. Neurology 57:115–121

    Article  CAS  PubMed  Google Scholar 

  • Hewitt JE (2009) Abnormal glycosylation of dystroglycan in human genetic disease. Biochim Biophys Acta 1792:853–861

    Article  CAS  PubMed  Google Scholar 

  • Kanagawa M, Nishimoto A, Chiyonobu T, Takeda S, Miyagoe-Suzuki Y, Wang F, Fujikake N, Taniguchi M, Lu Z, Tachikawa M, Nagai Y, Tashiro F, Miyazaki J, Tajima Y, Takeda S, Endo T, Kobayashi K, Campbell KP, Toda T (2009) Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy. Hum Mol Genet 18:621–631

    CAS  PubMed  Google Scholar 

  • Kanagawa M, Yu CC, Ito C, Fukada SI, Hozoji-Inada M, Chiyo T, Kuga A, Matsuo M, Sato K, Yamaguchi M, Ito T, Ohtsuka Y, Katanosaka Y, Miyagoe-Suzuki Y, Naruse K, Kobayashi K, Okada T, Takeda SI, Toda T (2013) Impaired viability of muscle precursor cells in muscular dystrophy with glycosylation defects and amelioration of its severe phenotype by limited gene expression. Hum Mol Genet 22:3003–3015. doi:10.1093/hmg/ddt157

    Article  CAS  PubMed  Google Scholar 

  • Kawahara G, Guyon JR, Nakamura Y, Kunkel LM (2010) Zebrafish models for human FKRP muscular dystrophies. Hum Mol Genet 19:623–633

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, Segawa M, Yoshioka M, Saito K, Osawa M, Hamano K, Sakakihara Y, Nonaka I, Nakagome Y, Kanazawa I, Nakamura Y, Tokunaga K, Toda T (1998) An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394:388–392

    Article  CAS  PubMed  Google Scholar 

  • Kuga A, Kanagawa M, Sudo A, Chan YM, Tajiri M, Manya H, Kikkawa Y, Nomizu M, Kobayashi K, Endo T, Lu QL, Wada Y, Toda T (2012) Absence of post-phosphoryl modification in dystroglycanopathy mouse models and wild-type tissues expressing non-laminin binding form of α-dystroglycan. J Biol Chem 287:9560–9567

    Article  CAS  PubMed  Google Scholar 

  • Kurahashi H, Taniguchi M, Meno C, Taniguchi Y, Takeda S, Horie M, Otani H, Toda T (2005) Basement membrane fragility underlies embryonic lethality in fukutin-null mice. Neurobiol Dis 19:208–217

    Article  CAS  PubMed  Google Scholar 

  • Lin YY, White RJ, Torelli S, Cirak S, Muntoni F, Stemple DL (2011) Zebrafish Fukutin family proteins link the unfolded protein response with dystroglycanopathies. Hum Mol Genet 20:1763–1775

    Article  CAS  PubMed  Google Scholar 

  • Lynch TA, le Lam T, Man NT, Kobayashi K, Toda T, Morris GE (2012) Detection of the dystroglycanopathy protein, fukutin, using a new panel of site-specific monoclonal antibodies. Biochem Biophys Res Commun 424:354–357

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto H, Noguchi S, Sugie K, Ogawa M, Murayama K, Hayashi YK, Nishino I (2004) Subcellular localization of fukutin and fukutin-related protein in muscle cells. J Biochem 135:709–712

    Article  CAS  PubMed  Google Scholar 

  • Michele DE, Campbell KP (2003) Dystrophin-glycoprotein complex: post-translational processing and dystroglycan function. J Biol Chem 278:15457–15460

    Article  CAS  PubMed  Google Scholar 

  • Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD, Satz JS, Dollar J, Nishino I, Kelley RI, Somer H, Straub V, Mathews KD, Moore SA, Campbell KP (2002) Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418:417–422

    Article  CAS  PubMed  Google Scholar 

  • Roscioli T, Kamsteeg EJ, Buysse K, Maystadt I, van Reeuwijk J, van den Elzen C, van Beusekom E, Riemersma M, Pfundt R, Vissers LE, Schraders M, Altunoglu U, Buckley MF, Brunner HG, Grisart B, Zhou H, Veltman JA, Gilissen C, Mancini GM, Delrée P, Willemsen MA, Ramadža DP, Chitayat D, Bennett C, Sheridan E, Peeters EA, Tan-Sindhunata GM, de Die-Smulders CE, Devriendt K, Kayserili H, El-Hashash OA, Stemple DL, Lefeber DJ, Lin YY, van Bokhoven H (2012) Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan. Nat Genet 44:581–585

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tachikawa M, Kanagawa M, Yu CC, Kobayashi K, Toda T (2012) Mislocalization of fukutin protein by disease-causing missense mutations can be rescued with treatments directed at folding amelioration. J Biol Chem 287:8398–8406

    Article  CAS  PubMed  Google Scholar 

  • Takeda S, Kondo M, Sasaki J, Kurahashi H, Kano H, Arai K, Misaki K, Fukui T, Kobayashi K, Tachikawa M, Imamura M, Nakamura Y, Shimizu T, Murakami T, Sunada Y, Fujikado T, Matsumura K, Terashima T, Toda T (2003) Fukutin is required for maintenance of muscle integrity, cortical histiogenesis and normal eye development. Hum Mol Genet 12:1449–1459

    Article  CAS  PubMed  Google Scholar 

  • Taniguchi-Ikeda M, Kobayashi K, Kanagawa M, Yu CC, Mori K, Oda T, Kuga A, Kurahashi H, Akman HO, DiMauro S, Kaji R, Yokota T, Takeda S, Toda T (2011) Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy. Nature 478:127–131

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Thornhill P, Bassett D, Lochmüller H, Bushby K, Straub V (2008) Developmental defects in a zebrafish model for muscular dystrophies associated with the loss of fukutin-related protein (FKRP). Brain 131:1551–1561

    Article  PubMed  Google Scholar 

  • Toda T, Kobayashi K, Takeda S, Sasaki J, Kurahashi H, Kano H, Tachikawa M, Wang F, Nagai Y, Taniguchi K, Taniguchi M, Sunada Y, Terashima T, Endo T, Matsumura K (2003) Fukuyama-type congenital muscular dystrophy (FCMD) and alpha-dystroglycanopathy. Congenit Anom (Kyoto) 43:97–104

    Article  CAS  Google Scholar 

  • Torelli S, Brown SC, Brockington M, Dolatshad NF, Jimenez C, Skordis L, Feng LH, Merlini L, Jones DH, Romero N, Wewer U, Voit T, Sewry CA, Noguchi S, Nishino I, Muntoni F (2005) Sub-cellular localisation of fukutin related protein in different cell lines and in the muscle of patients with MDC1C and LGMD2I. Neuromuscul Disord 15:836–843

    Article  PubMed  Google Scholar 

  • Willer T, Lee H, Lommel M, Yoshida-Moriguchi T, de Bernabe DB, Venzke D, Cirak S, Schachter H, Vajsar J, Voit T, Muntoni F, Loder AS, Dobyns WB, Winder TL, Strahl S, Mathews KD, Nelson SF, Moore SA, Campbell KP (2012) ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. Nat Genet 44:575–580

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wood AJ, Müller JS, Jepson CD, Laval SH, Lochmüller H, Bushby K, Barresi R, Straub V (2011) Abnormal vascular development in zebrafish models for fukutin and FKRP deficiency. Hum Mol Genet 20:4879–4890

    Article  CAS  PubMed  Google Scholar 

  • Xiong H, Kobayashi K, Tachikawa M, Manya H, Takeda S, Chiyonobu T, Fujikake N, Wang F, Nishimoto A, Morris GE, Nagai Y, Kanagawa M, Endo T, Toda T (2006) Molecular interaction between fukutin and POMGnT1 in the glycosylation pathway of alpha-dystroglycan. Biochem Biophys Res Commun 350:935–941

    Article  CAS  PubMed  Google Scholar 

  • Yoshida-Moriguchi T, Yu L, Stalnaker SH, Davis S, Kunz S, Madson M, Oldstone MB, Schachter H, Wells L, Campbell KP (2010) O-mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding. Science 327:88–92

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology and Cell Biology, Division of Molecular Brain Science, Kobe University, Graduate School of Medicine, 7-5-1 Kusunoki-chou, 650-0017, Chuo-ku, Kobe, Japan

    Dr. Motoi Kanagawa

  2. Department of Neurology / Department of Physiology and Cell Biology, Division of Molecular Brain Science, Kobe University, Graduate School of Medicine, 7-5-1 Kusunoki-chou, 650-0017, Chuo-ku, Kobe, Japan

    Prof. Tatsushi Toda

Authors
  1. Dr. Motoi Kanagawa
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  2. Prof. Tatsushi Toda
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Corresponding author

Correspondence to Motoi Kanagawa .

Editor information

Editors and Affiliations

  1. RIKEN-Max-Planck Joint Research Center for Systems Chemical Biology, RIKEN, Wako, Saitama, Japan

    Naoyuki Taniguchi

  2. Department of Biochemistry, Kochi University, Medical School, Nankoku, Kochi, Japan

    Koichi Honke

  3. Sanford Burnham Medical Research Institute, La Jolla, California, USA

    Minoru Fukuda

  4. Research Center for Medical Glycoscience (RCMG), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan

    Hisashi Narimatsu

  5. RIKEN-Max-Planck Joint Research Center for Systems Chemical Biology, RIKEN, Wako, Saitama, Japan

    Yoshiki Yamaguchi

  6. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

    Takashi Angata

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Kanagawa, M., Toda, T. (2014). Fukutin and Fukutin-Related Protein (FKRP). In: Taniguchi, N., Honke, K., Fukuda, M., Narimatsu, H., Yamaguchi, Y., Angata, T. (eds) Handbook of Glycosyltransferases and Related Genes. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54240-7_141

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