*128239 DYSTROPHIN-ASSOCIATED GLYCOPROTEIN 1;
DAG1
Alternative
titles; symbols
DAG
DYSTROGLYCAN, ALPHA
AGRIN RECEPTOR; AGRNR
table OF
CONTENTS
"18
MEDLINE Citations"
"8 Protein Links"
"3 Nucleotide Links"
"2 Genome Links" "Gene
Map" "GDB"
"Jackson
Labs Mouse Database" "Nomenclature
Database"
Gene Map Locus: 3p21
Note: pressing the symbol will find the
citations in MEDLINE whose text most closely
matches the text of the preceding OMIM paragraph,
using the Entrez MEDLINE neighboring function.
TEXT
Ibraghimov-Beskrovnaya et
al. (1992) demonstrated that the transmembrane
43K and extracellular 156K dystrophin-associated
glycoproteins are encoded by a single messenger RNA
and that the extracellular 156K DAG binds laminin.
Thus, the 156K DAG is a laminin-binding
glycoprotein that may provide linkage between the
sarcolemma and extracellular matrix. The dramatic
reduction in the 156K DAG in Duchenne muscular
dystrophy (310200)
led to a loss of linkage between the sarcolemma and
extracellular matrix, rendering muscle fibers more
susceptible to necrosis. Ibraghimov-Beskrovnaya et
al. (1992, 1992,
1993) mapped the DAG gene
to chromosome 3 by Southern blot analysis of
human/Chinese hamster somatic cell hybrid DNAs. One
hybrid cell line with an isochromosome 3q was
negative, suggesting location of the gene on 3p.
The regional assignment was confirmed and further
refined by fluorescence in situ hybridization, the
localization being 3p21. The coding sequence of the
DAG1 gene is organized into 2 exons, separated by a
large intron (Ibraghimov-Beskrovnaya
et al., 1993). The predicted amino acid
sequence of human and rabbit dystroglycan are 93%
identical, with predicted glycosylation sites being
conserved. Human dystroglycan is expressed in a
variety of fetal and adult tissues. The muscle and
nonmuscle isoforms of dystroglycan differ by
carbohydrate moieties but not protein sequence.
"18 MEDLINE Neighbors"
Agrin (103320)
is a component of the synaptic basal lamina which
induces the aggregation of acetylcholine receptors
and other elements of the postsynaptic membrane.
Ma et al. (1993)
determined the localization, binding
characteristics, and biochemical profile of the
agrin receptor in Torpedo electric organ membranes
and defined domains of agrin that bind this
receptor.
"30 MEDLINE Neighbors"
Campanelli et al.
(1994) and Gee et al.
(1994) presented evidence that the
dystrophin-associated glycoprotein
(alpha-dystroglycan) functions as an agrin
receptor. Utrophin (128240)
colocalizes with agrin-induced acetylcholine
receptor clusters. Agrin may function by initiating
or stabilizing a synapse-specific membrane
cytoskeleton that in turn serves as a scaffold upon
which synaptic molecules are concentrated.
Sealock and Froehner
(1994) reviewed the evidence that
alpha-dystroglycan is an agrin-binding protein and
the functional implications of this.
"30 MEDLINE Neighbors"
Dystroglycan is a candidate gene for the site of
the mutation in autosomal recessive muscular
dystrophies. Indeed, Matsumura
et al. (1993) demonstrated deficient expression
of dystrophin-associated glycoprotein in the
Japanese Fukuyama-type of congenital muscular
dystrophy (FCMD; 253800).
The 156DAG/43DAG gene is expressed in both muscle
and brain. Matsumura et al.
(1992) suggested that an abnormality of
dystrophin-associated proteins in the sarcolemma is
a common denominator in the pathologic processes
leading to muscle cell necrosis in 3 forms of
severe muscular dystrophy: Duchenne, Japanese
Fukuyama-type, and North African Duchenne-like
autosomal recessive type (253700).
Arahata et al. (1993)
found preservation of immunostaining for 43DAG in
FCMD at the plasma membrane of the muscle fibers.
On the other hand, they found reduced laminin M (or
merosin (156225),
a striated muscle-specific basal-lamina-associated
protein) in most muscle fibers of FCMD, suggesting
that it may have an early or primary role in the
pathogenesis of the disorder.
"30 MEDLINE Neighbors"
Matsumura et al.
(1993) showed that truncation of the dystrophin
molecule with loss of the C-terminal domains can
lead to severe muscular dystrophy, even when
truncated dystrophin is demonstrable in the
subsarcolemmal cytoskeleton. The reason is that the
C-terminal domains are involved in the interaction
with the large oligomeric complex of sarcolemmal
glycoproteins, including dystroglycan.
"30 MEDLINE Neighbors"
Tinsley et al. (1994)
reviewed the 'increasing complexity of the
dystrophin-associated protein complex.' Although
the exact function of dystrophin remained to be
determined, analysis of its interaction with this
large oligomeric protein complex at the sarcolemma
and the identification of a structurally related
protein, utrophin (128240),
were leading to the identification of candidate
genes for various neuromuscular disorders.
"30 MEDLINE Neighbors"
Yamada et al. (1996)
showed that dystroglycan is a dual receptor for
agrin and laminin-2 in the Schwann cell membrane.
Laminin-2 is composed of the alpha-2 (156225),
beta-1 (150240),
and gamma-1 (150290)
laminin chains.
Gorecki et al. (1994)
demonstrated that the Dag1 gene is located on mouse
chromosome 9 in a region of conserved synteny with
human 3p. The location was consistent with a
possibility that dystroglycan mutations are
involved in either of 2 mouse neurologic mutations,
'ducky' (du) or 'tippy' (tip).
To understand better the function of
dystroglycan in development and disease, Williamson
et al. (1997) generated a null allele of the
Dag1 gene in mice. Heterozygous mice were viable
and fertile. In contrast, homozygous embryos
exhibited gross developmental abnormalities
beginning around 6.5 days' gestation. They found
that an early defect in the development of
homozygous embryos was a disruption of the Reichert
membrane, an extra-embryonic basement membrane.
Consistent with the functional defects observed in
Reichert membrane, dystroglycan protein was
localized in apposition to this structure in normal
egg cylinder-stage embryos. They also showed that
the localization of 2 critical structural elements
of Reichert membrane, laminin and collagen IV, were
specifically disrupted in the homozygous Dag1
embryos. The data indicated that dystroglycan is
required for the development of Reichert membrane
and that disruption of basement membrane
organization is a common feature of muscular
dystrophies linked to the dystrophin-glycoprotein
complex (DGC).
"30 MEDLINE Neighbors"
As detailed earlier, alpha-dystroglycan
(alpha-DG) is a component of the dystroglycan
complex, which is involved in early development and
morphogenesis and in the pathogenesis of muscular
dystrophies. Rambukkana et
al. (1998) showed that alpha-DG serves as a
Schwann cell receptor for Mycobacterium leprae, the
causative organism of leprosy. They found that M.
leprae specifically binds to alpha-DG only in the
presence of the G domain of the alpha-2 chain of
laminin-2. Native alpha-DG competitively inhibited
the laminin-2-mediated M. leprae binding to primary
Schwann cells. Thus, M. leprae may use linkage
between the extracellular matrix and the
cytoskeleton through laminin-2 and alpha-DG for its
interaction with Schwann cells. The neuropathy of
leprosy is caused, in part, by invasion of
peripheral nerves by M. leprae. The Schwann cell is
an important target for bacterial invasion. In the
endoneurium of peripheral nerves, Schwann cells are
covered by basal lamina, composed of laminin, type
IV collagen, entactin/nidogen, and heparan sulfate
proteoglycans. Similarly, Cao
et al. (1998) found that alpha-DG serves as a
receptor for lymphocytic choriomeningitis virus
(LCMV) and for Lassa fever virus (LFV). They
purified a peripheral membrane protein that is
interactive with LCMV from cells permissive to
infection by this virus. Tryptic peptides from this
protein were determined to be alpha-DG. Several
strains of LCMV and other arenaviruses, including
LFV, Oliveros, and Mobala, bound to purified
alpha-DG protein. Soluble alpha-DG blocked both
LCMV and LFV infection. Cells bearing a null
mutation of the gene encoding DG were resistant to
LCMV infection, and reconstitution of DG expression
in null mutant cells restored susceptibility to
LCMV infection. Thus, alpha-DG is a cellular
receptor for both LCMV and LFV.
"30 MEDLINE Neighbors"
A single gene encodes alpha-dystroglycan and
beta-dystroglycan, which are derived from a
precursor polypeptide by posttranslational
cleavage. Beta-dystroglycan is an integral membrane
protein, whereas alpha-dystroglycan is
membrane-associated through its noncovalent
interaction with the extracellular domain of
beta-dystroglycan. The alpha- and
beta-dystroglycans provide important physical
linkages between components of basement membranes
and cytoplasmic proteins that bind to the actin
cytoskeleton. As reviewed by Spear
(1998), in skeletal and cardiac muscle,
structural integrity of the sarcolemma appears to
depend in part on binding of the cytoplasmic
protein dystrophin (310200)
to both actin and the cytoplasmic tail of
beta-dystroglycan and binding of alpha-dystroglycan
to laminin-2 in the basal lamina. Laminins are
composed of 3 polypeptide chains designated alpha,
beta, and gamma. The multiple isoforms of laminin
differ in their constituent chains. Laminin-2 is
composed of alpha-2, beta-1, and gamma-1.
Homozygous deletion of the gene encoding
dystroglycan is lethal at the embryonic stage in
mice (Williamson et al.,
1997) and would presumably also be lethal in
humans.
"30 MEDLINE Neighbors"
Henry and Campbell
(1998) investigated the function of
dystroglycan, a cell surface laminin receptor
expressed by cells contacting basement membranes in
developing and adult tissues, by generating
DAG1-null embryonic stem cells. They found that
DAG1 is required for the formation of a basement
membrane in embryoid bodies. These results further
indicated that dystroglycan-laminin interactions
are prerequisite for the deposition of other
basement membrane proteins. Dystroglycan may exert
its influence on basement membrane assembly by
binding soluble laminin and organizing it on the
cell surface.
"30 MEDLINE Neighbors"
REFERENCES
- 1. Arahata, K.;
Hayashi, Y. K.; Mizuno, Y.; Yoshida, M.; Ozawa,
E. :
- Dystrophin-associated glycoprotein
and dystrophin co-localisation at sarcolemma in
Fukuyama congenital muscular dystrophy.
(Letter) Lancet 342: 623-624,
1993.
PubMed ID : 8102757
- 2. Campanelli, J.
T.; Roberds, S. L.; Campbell, K. P.; Scheller,
R. H. :
- A role for dystrophin-associated
glycoproteins and utrophin in agrin-induced AChR
clustering. Cell 77: 663-674,
1994.
PubMed ID : 8205616
- 3. Cao, W.; Henry,
M. D.; Borrow, P.; Yamada, H.; Elder, J. H.;
Ravkov, E. V.; Nichol, S. T.; Compans, R. W.;
Campbell, K. P.; Oldstone, M. B. A. :
- Identification of alpha-dystroglycan
as a receptor for lymphocytic choriomeningitis
virus and Lassa fever virus.
Science 282: 2079-2081, 1998.
PubMed ID : 9851928
- 4. Gee, S. H.;
Montanaro, F.; Lindenbaum, M. H.; Carbonetto, S.
:
- Dystroglycan-alpha, a
dystrophin-associated glycoprotein, is a
functional agrin receptor.
Cell 77: 675-686, 1994.
PubMed ID : 8205617
- 5. Gorecki, D. C.;
Derry, J. M. J.; Barnard, E. A. :
- Dystroglycan: brain localisation and
chromosome mapping in the mouse.
Hum. Molec. Genet. 3: 1589-1597,
1994.
PubMed ID : 7833916
- 6. Henry, M. D.;
Campbell, K. P. :
- A role for dystroglycan in basement
membrane assembly. Cell 95:
859-970, 1998.
PubMed ID : 9865703
- 7.
Ibraghimov-Beskrovnaya, O.; Ervasti, J. M.;
Leveille, C. J.; Slaughter, C. A.; Sernett, S.
W.; Campbell, K. P. :
- Primary structure of
dystrophin-associated glycoproteins linking
dystrophin to the extracellular matrix.
Nature 355: 696-702, 1992.
PubMed ID : 1741056
- 8.
Ibraghimov-Beskrovnaya, O.; Milatovich, A.;
Ozcelik, T.; Yang, B.; Francke, U.; Campbell, K.
P. :
- Dystroglycan: tissue distribution,
human muscle cDNA, genomic structure and
chromosome mapping. (Abstract) Am.
J. Hum. Genet. 51 (suppl.): A130 only,
1992.
- 9.
Ibraghimov-Beskrovnaya, O.; Milatovich, A.;
Ozcelik, T.; Yang, B.; Koepnick, K.; Francke,
U.; Campbell, K. P. :
- Human dystroglycan: skeletal muscle
cDNA, genomic structure, origin of tissue
specific isoforms and chromosomal
localization. Hum. Molec.
Genet. 2: 1651-1657, 1993.
PubMed ID : 8268918
- 10. Ma, J.; Nastuk,
M. A.; McKechnie, B. A.; Fallon, J. R. :
- The agrin receptor: localization in
the postsynaptic membrane, interaction with
agrin, and relationship to the acetylcholine
receptor. J. Biol. Chem. 268:
25108-25117, 1993.
PubMed ID : 8227074
- 11. Matsumura, K.;
Nonaka, I.; Campbell, K. P. :
- Abnormal expression of
dystrophin-associated proteins in Fukuyama-type
congenital muscular dystrophy.
Lancet 341: 521-522, 1993.
PubMed ID : 8094772
- 12. Matsumura, K.;
Tome, F. M. S.; Collin, H.; Azibi, K.; Chaouch,
M.; Kaplan, J.-C.; Fardeau, M.; Campbell, K. P.
:
- Deficiency of the 50K
dystrophin-associated glycoprotein in severe
childhood autosomal recessive muscular
dystrophy. Nature 359:
320-322, 1992.
PubMed ID : 1406935
- 13. Matsumura, K.;
Tome, F. M. S.; Ionasescu, V.; Ervasti, J. M.;
Anderson, R. D.; Romero, N. B.; Simon, D.;
Recan, D.; Kaplan, J.-C.; Fardeau, M.; Campbell,
K. P. :
- Deficiency of dystrophin-associated
proteins in Duchenne muscular dystrophy patients
lacking COOH-terminal domains of
dystrophin. J. Clin. Invest.
92: 866-871, 1993.
PubMed ID : 8349821
- 14. Rambukkana, A.;
Yamada, H.; Zanazzi, G.; Mathus, T.; Salzer, J.
L.; Yurchenco, P. D.; Campbell, K. P.;
Fischetti, V. A. :
- Role of alpha-dystroglycan as a
Schwann cell receptor for Mycobacterium
leprae. Science 282:
2076-2078, 1998.
PubMed ID : 9851927
- 15. Sealock, R.;
Froehner, S. C. :
- Dystrophin-associated proteins and
synapse formation: is alpha-dystroglycan the
agrin receptor?. Cell 77:
617-619, 1994.
PubMed ID : 8205610
- 16. Spear, P. G.
:
- A welcome mat for leprosy and Lassa
fever. Science 282: 1999-2000,
1998.
PubMed ID : 9874652
- 17. Tinsley, J. M.;
Blake, D. J.; Zuellig, R. A.; Davies, K. E.
:
- Increasing complexity of the
dystrophin-associated protein complex.
Proc. Nat. Acad. Sci. 91: 8307-8313,
1994.
PubMed ID : 8078878
- 18. Williamson, R.
A.; Henry, M. D.; Daniels, K. J.; Hrstka, R. F.;
Lee, J. C.; Sunada, Y.; Ibraghimov-Beskrovnaya,
O.; Campbell, K. P. :
- Dystroglycan is essential for early
embryonic development: disruption of Reichert's
membrane in Dag1-null mice. Hum.
Molec. Genet. 6: 831-841, 1997.
PubMed ID : 9175728
- 19. Yamada, H.;
Denzer, A. J.; Hori, H.; Tanaka, T.; Anderson,
L. V. B.; Fujita, S.; Fukuta-Ohi, H.; Shimizu,
T.; Ruegg, M. A.; Matsumura, K. :
- Dystroglycan is a dual receptor for
agrin and laminin-2 in Schwann cell
membrane. J. Biol. Chem. 271:
23418-23423, 1996.
PubMed ID : 8798547
CONTRIBUTORS
Stylianos E. Antonarakis - updated :
12/22/1998
Victor A. McKusick - updated : 12/9/1998
Victor A. McKusick - updated : 6/23/1997
Mark H. Paalman - updated : 10/14/1996
CREATION DATE
Victor A. McKusick : 9/27/1994
EDIT HISTORY
carol : 4/16/1999
mgross : 3/17/1999
carol : 12/22/1998
alopez : 12/10/1998
terry : 12/9/1998
terry : 8/13/1998
jenny : 6/23/1997
terry : 6/19/1997
mark : 10/15/1996
terry : 10/14/1996
mark : 10/14/1996
terry : 11/16/1994
carol : 9/27/1994
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