Advertisement

Fukutin and Fukutin-Related Protein (FKRP)

  • Motoi Kanagawa
  • Tatsushi Toda
Reference work entry

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.

Keywords

Muscular Dystrophy Duchenne Muscular Dystrophy Congenital Muscular Dystrophy Abnormal Glycosylation Glycosylation Defect 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 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 132:439–451PubMedCrossRefGoogle Scholar
  2. Aravind L, Koonin EV (1999) The fukutin protein family – predicted enzymes modifying cell-surface molecules. Curr Biol 9:R836–R837PubMedCrossRefGoogle Scholar
  3. Barresi R, Campbell KP (2006) Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci 119:199–207PubMedCrossRefGoogle Scholar
  4. Beedle AM, Nienaber PM, Campbell KP (2007) Fukutin-related protein associates with the sarcolemmal dystrophin-glycoprotein complex. J Biol Chem 282:16713–16717PubMedCrossRefGoogle Scholar
  5. 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 122:3330–3342PubMedCentralPubMedCrossRefGoogle Scholar
  6. Breton C, Imberty A (1999) Structure/function studies of glycosyltransferases. Curr Opin Struct Biol 9:563–571PubMedCrossRefGoogle Scholar
  7. 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 10:2851–2859PubMedCrossRefGoogle Scholar
  8. 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 69:1198–1209PubMedCentralPubMedCrossRefGoogle Scholar
  9. 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 19:3995–4006PubMedCrossRefGoogle Scholar
  10. 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 272:2156–2162PubMedCrossRefGoogle Scholar
  11. 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 15:416–426PubMedCrossRefGoogle Scholar
  12. 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 309:370–378PubMedCrossRefGoogle Scholar
  13. 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 11:3319–3331PubMedCrossRefGoogle Scholar
  14. Fukuyama Y, Osawa M, Suzuki H (1981) Congenital progressive muscular dystrophy of the Fukuyama type – clinical, genetic and pathological considerations. Brain Dev 3:1–29PubMedCrossRefGoogle Scholar
  15. 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 130:2725–2735PubMedCrossRefGoogle Scholar
  16. Godfrey C, Foley AR, Clement E, Muntoni F (2011) Dystroglycanopathies: coming into focus. Curr Opin Genet Dev 21:278–285PubMedCrossRefGoogle Scholar
  17. 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 364:939–946PubMedCentralPubMedCrossRefGoogle Scholar
  18. 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 57:115–121PubMedCrossRefGoogle Scholar
  19. Hewitt JE (2009) Abnormal glycosylation of dystroglycan in human genetic disease. Biochim Biophys Acta 1792:853–861PubMedCrossRefGoogle Scholar
  20. 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 18:621–631PubMedGoogle Scholar
  21. 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/ddt157PubMedCrossRefGoogle Scholar
  22. Kawahara G, Guyon JR, Nakamura Y, Kunkel LM (2010) Zebrafish models for human FKRP muscular dystrophies. Hum Mol Genet 19:623–633PubMedCrossRefGoogle Scholar
  23. 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 394:388–392PubMedCrossRefGoogle Scholar
  24. 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 287:9560–9567PubMedCrossRefGoogle Scholar
  25. 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 19:208–217PubMedCrossRefGoogle Scholar
  26. 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 20:1763–1775PubMedCrossRefGoogle Scholar
  27. 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 424:354–357PubMedCrossRefGoogle Scholar
  28. 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 135:709–712PubMedCrossRefGoogle Scholar
  29. Michele DE, Campbell KP (2003) Dystrophin-glycoprotein complex: post-translational processing and dystroglycan function. J Biol Chem 278:15457–15460PubMedCrossRefGoogle Scholar
  30. 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 418:417–422PubMedCrossRefGoogle Scholar
  31. 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 44:581–585PubMedCentralPubMedCrossRefGoogle Scholar
  32. 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 287:8398–8406PubMedCrossRefGoogle Scholar
  33. 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 12:1449–1459PubMedCrossRefGoogle Scholar
  34. 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 478:127–131PubMedCentralPubMedCrossRefGoogle Scholar
  35. 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 131:1551–1561PubMedCrossRefGoogle Scholar
  36. 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) 43:97–104CrossRefGoogle Scholar
  37. 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 15:836–843PubMedCrossRefGoogle Scholar
  38. 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 44:575–580PubMedCentralPubMedCrossRefGoogle Scholar
  39. 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 20:4879–4890PubMedCrossRefGoogle Scholar
  40. 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 350:935–941PubMedCrossRefGoogle Scholar
  41. 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 327:88–92PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  1. 1.Department of Physiology and Cell Biology, Division of Molecular Brain ScienceKobe University, Graduate School of MedicineChuo-kuJapan
  2. 2.Department of Neurology / Department of Physiology and Cell Biology, Division of Molecular Brain ScienceKobe University, Graduate School of MedicineChuo-kuJapan

Personalised recommendations