Original article| Volume 26, ISSUE 7, P469-479, October 2004

Download started.


Fukutin expression in mouse non-muscle somatic organs: its relationship to the hypoglycosylation of α-dystroglycan in Fukuyama-type congenital muscular dystrophy


      Resent studies suggest that hypoglycosylation of α-dystroglycan (α-DG) may play an essential role in the pathogenesis of Fukuyama-type congenital muscular dystrophy (FCMD), which is caused by defects in the fukutin gene and characterized by dystrophic changes in the skeletal muscles and dysplastic lesions in the central nervous system. α-DG is expressed in many organs in addition to muscle and brain, although these organs are not affected in FCMD. To elucidate whether or not fukutin protein is involved in the glycosylation of α-DG in non-muscle somatic organs, we examined the distribution pattern of fukutin in developing and adult mouse tissues. The fukutin antisera labeled the acinar cells of the pancreas, the renal glomerular and tubular cells, and the epithelium of the bronchi, salivary gland, alimentary tract and skin in both fetal and adult mice. This distribution pattern was also confirmed by in situ hybridization. Antisera against α-DG and β-DG labeled the same cellular populations in each organ, especially along the cell surface membrane. We also examined the glycosylation status of α-DG in autopsied FCMD cases (n=5) and found evidence of hypoglycosylation in the kidney, lung, skin and intestine. These results suggest that fukutin protein is involved in the glycosylation process of α-DG in non-muscle somatic organs both during development and in the adult. It is unclear why muscle and brain symptoms predominate in FCMD, however re-evaluation of the functions of α-DG and fukutin protein in non-muscle somatic organs may provide valuable insight.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kobayashi K.
        • Nakahori Y.
        • Miyake M.
        • Matsumura K.
        • Kondo-Iida E.
        • Nomura Y.
        • et al.
        An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy.
        Nature. 1998; 394: 388-392
        • Nonaka I.
        • Chou S.M.
        Congenital muscular dystrophy.
        in: Vinken P.J. Bruyn G.W. Handbook of clinical neurology. Disease of muscle, part II. vol. 41. North-Holland, Amsterdam1979: 27-50
        • Fukuyama Y.
        • Osawa M.
        • Suzuki H.
        Congenital progressive muscular dystrophy of the Fukuyama type—clinical, genetic and pathological considerations.
        Brain Dev. 1981; 3: 1-29
        • Aravind L.
        • Koonin E.V.
        The fukutin protein family—predicted enzymes modifying cell-surface molecules.
        Curr Biol. 1999; 9: R836-R837
        • Michele D.E.
        • Barresi R.
        • Kanagawa M.
        • Saito F.
        • Cohn R.D.
        • Satz J.S.
        • et al.
        Post-translational disruption of dytroglycan–ligand interactions in congenital muscular dystrophies.
        Nature. 2002; 418: 417-422
        • Yoshida A.
        • Kobayashi K.
        • Manya H.
        • Taniguchi K.
        • Kano H.
        • Mizuno M.
        • et al.
        Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1.
        Dev Cell. 2001; 1: 717-724
        • De Bernabé D.B.-V.
        • Currier S.
        • Steinbrecher A.
        • Celli J.
        • van Beusekom E.
        • van der Zwaag B.
        • et al.
        Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker–Warburg syndrome.
        Am J Hum Genet. 2002; 71: 1033-1043
        • Grewal P.K.
        • Holzfeind P.J.
        • Bittner R.
        • Hewitt J.E.
        Mutant glycosyltransferase and altered glycosylation of α-dystroglycan in the myodystrophy mouse.
        Nat Genet. 2001; 28: 151-154
        • Ibraghimov-Beskrovnaya O.
        • Ervasti J.M.
        • Leveille J.
        • Slaughter C.A.
        • Sernett S.W.
        • Campbell K.P.
        Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix.
        Nature. 1992; 355: 696-702
        • Ervasti J.M.
        • Campbell K.P.
        A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin.
        J Cell Biol. 1993; 122: 809-823
        • Henry M.D.
        • Campbell K.P.
        Dystroglycan inside and out.
        Curr Opin Cell Biol. 1999; 11: 602-607
        • Moore S.A.
        • Saito F.
        • Chen J.
        • Michele D.E.
        • Henry M.D.
        • Messing A.
        • et al.
        Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy.
        Nature. 2002; 418: 422-425
        • Schofield J.N.
        • Górecki D.C.
        • Blake D.J.
        • Davies K.
        • Edwards Y.H.
        Dystroglycan mRNA expression during normal and mdx mouse embryogenesis: a comparison with utrophin and the apo-dystrophins.
        Dev Dyn. 1995; 204: 1778-1785
        • Durbeej M.
        • Henry M.D.
        • Ferletta M.
        • Campbell K.P.
        • Ekblom P.
        Distribution of dystroglycan in normal adult mouse tissues.
        J Histochem Cytochem. 1998; 46: 449-457
        • Henry M.D.
        • Campbell K.P.
        A role for dystroglycan in basement membrane assembly.
        Cell. 1998; 95: 859-870
        • Montanaro F.
        • Lindenbaum M.
        • Carbonetto S.
        α-dystroglycan is a laminin receptor involved in extracellular matrix assembly on myotubes and muscle cell viability.
        J Cell Biol. 1999; 145: 1325-1340
        • Yang B.
        • Jung D.
        • Motto D.
        • Meyer J.
        • Koretzky G.
        • Campbell K.P.
        SH3 domain-mediated interaction of dystroglycan and Grb2.
        J Biol Chem. 1995; 270: 11711-11714
        • Williamson R.A.
        • Henry M.D.
        • Daniels K.J.
        • Hrstka R.F.
        • Lee J.C.
        • Sunada Y.
        • et al.
        Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice.
        Hum Mol Genet. 1997; 6: 831-841
        • Durbeej M.
        • Talts J.F.
        • Henry M.D.
        • Yurchenco P.D.
        • Campbell K.P.
        • Ekblom P.
        Dystroglycan binding to laminin alpha1LG4 module influences epithelial morphogenesis of salivary gland and lung in vitro.
        Differentiation. 2001; 69: 121-134
        • Durbeej M.
        • Ekblom P.
        Dystroglycan and laminins: glycoconjugates involved in branching epithelial morphogenesis.
        Exp Lung Res. 1997; 23: 109-118
        • Durbeej M.
        • Larsson E.
        • Ibraghimov-Beskorvnaya O.
        • Roberds S.L.
        • Campbell K.P.
        • Ekblom P.
        Non-muscle α-dystroglycan is involved in epithelial development.
        J Cell Biol. 1995; 130: 79-91
        • White S.R.
        • Wojcik K.R.
        • Gruenert D.
        • Sun S.
        • Dorscheid D.R.
        Airway epithelial cell wound repair mediated by α-dystroglycan.
        Am J Respir Cell Mol Biol. 2001; 24: 179-186
        • Gesemann M.
        • Brancaccio A.
        • Schumacher B.
        • Ruegg M.A.
        Agrin is a high-affinity binding protein of dystroglycan in non-muscle tissue.
        J Biol Chem. 1998; 273: 600-605
        • Gee S.H.
        • Blacher R.W.
        • Douville P.J.
        • Provost P.R.
        • Yurchenco P.D.
        • Carbonetto S.
        Laminin-binding protein 120 from brain is closely related to the dystrophin-associated glycoprotein, dystroglycan, and binds with high affinity to the major heparin binding domain of laminin.
        J Biol Chem. 1993; 268: 14972-14980
        • Leschziner A.
        • Moukhles H.
        • Lindenbaum M.
        • Gee S.H.
        • Butterworth J.
        • Campbell K.P.
        • et al.
        Neural regulation of α-dystroglycan biosynthesis and glycosylation in skeletal muscle.
        J Neurochem. 2000; 74: 70-80
        • Durbeej M.
        • Campbell K.P.
        Biochemical characterization of the epithelial dystroglycan complex.
        J Biol Chem. 1999; 274: 26609-26616
        • Saito K.
        • Osawa M.
        • Wang Z.P.
        • Ikeya K.
        • Fukuyama Y.
        • Kondo-Iida E.
        • et al.
        Haplotype–phenotype correlation in Fukuyama congenital muscular dystrophy.
        Am J Med Genet. 2000; 92: 184-190
        • Saito Y.
        • Kobayashi M.
        • Itoh M.
        • Saito K.
        • Mizuguchi M.
        • Sasaki H.
        • et al.
        Aberrant neuronal migration in the brainstem of Fukuyama-type congenital muscular dystrophy.
        J Neuropathol Exp Neurol. 2003; 62: 497-508
        • Yamamoto T.
        • Kato Y.
        • Karita M.
        • Takeiri H.
        • Muramatsu F.
        • Kobayashi M.
        • et al.
        Fukutin expression in glial cells and neurons: implication in the brain lesions of Fukuyama congenital muscular dystrophy.
        Acta Neuropathol. 2002; 104: 217-224
        • Saito Y.
        • Mizuguchi M.
        • Oka A.
        • Takashima S.
        Fukutin protein is expressed in neurons of the normal developing human brain but is reduced in Fukuyama-type congenital muscular dystrophy brain.
        Ann Neurol. 2000; 47: 756-764
        • Horie M.
        • Kobayashi K.
        • Takeda S.
        • Nakamura Y.
        • Lyons G.E.
        • Toda T.
        Isolation and characterization of the mouse ortholog of the Fukuyama-type congenital muscular dystrophy gene.
        Genomics. 2002; 80: 482-486
        • Hayashi Y.K.
        • Ogawa M.
        • Tagawa K.
        • Noguchi S.
        • Ishihara T.
        • Nonaka I.
        • et al.
        Selective deficiency of α-dystroglycan in Fukuyama-type congenital muscular dystrophy.
        Neurology. 2001; 57: 115-121
        • Kaufman M.H.
        The atlas of mouse development.
        Academic Press, San Diego, CA1995
        • Kaufman M.H.
        • Bard J.B.L.
        The anatomical basis of mouse development.
        Academic Press, San Diego, CA1999
        • Lidov H.G.W.
        • Kunkel L.M.
        Dystrophin and Dp140 in the adult rodent kidney.
        Lab Invest. 1998; 78: 11543-11551
        • Schofield J.
        • Houzelstein D.
        • Davies K.
        • Buckinhgam M.
        • Edwards Y.H.
        Expression of the dystrophin-related protein (utrophin) gene during mouse embryogenesis.
        Dev Dyn. 1993; 198: 254-264
        • Holt K.H.
        • Crosbie R.H.
        • Venzke D.P.
        • Campbell K.P.
        Biosynthesis of dystroglycan: processing of a precursor propeptide.
        FEBS Lett. 2000; 468: 79-83
        • Saito F.
        • Masaki T.
        • Kamakura K.
        • Anderson L.V.B.
        • Fujita S.
        • Fukuta Ohi H.
        • et al.
        Characterization of the transmembrane molecular architecture of the dystroglycan complex in schwann cells.
        J Biol Chem. 1999; 274: 8240-8246
        • Raats C.J.I.
        • van den Born J.
        • Bakker M.A.H.
        • Oppers-Walgreen B.
        • Pisa B.J.M.
        • Dijkman H.B.P.M.
        • et al.
        Expression of agrin, dystroglycan, and utrophin in normal renal tissue and in experimental glomerulopathies.
        Am J Pathol. 2000; 156: 1749-1765