(last modified January 14, 2006)
alpha- and ß-dystroglycan (DAG1), also known as cranin (Smalheiser & Kim) are ubiquitously expressed in various tissues. They are translated from a single mRNA as a 97 kDa protein which is proteolytically cleaved into two, closely associated peptides (Ibraghimov-Beskrovnaya, Smalheiser & Schwartz). alpha-Dystroglycan is an extra-cellular protein which binds to alpha-laminin, probably through its sugar chains, and to ß-dystroglycan. Laminin is a component of the basal lamina (extracellular matrix), comprised of three subunits: alpha, beta and gamma. The alpha-laminin (merosin) subunit binds to alpha-dystroglycan. ß-dystroglycan is a transmembrane protein which, outside the cell, binds to alpha-dystroglycan and, inside the cell, to the cysteine-rich domain and the first half of the carboxyl-terminal domain of dystrophin (together designated the dystroglycan binding (D-) domain). No human disease has yet been linked to dystroglycan mutations. Mice homozygously lacking dystroglycan show embryonic lethality, thought to arise from defects in extra-embryonic structures and their association with the extra-cellular matrix (Williamson).
Dystroglycan is a heavily glycosylated, peripheral membrane protein that directly binds, probably through its sugar chains, to alpha-laminin (an extracellular matrix protein) and to ß-dystroglycan. The proposed function of ß-dystroglycan is to provide a link between the subsarcolemmal cytoskeleton and the extra-cellular matrix.
Originally, dystroglycan was described by Smalheiser & Kim as "cranin". Later, Ervasti described the same protein as 156 (alpha-) and 43 kD (ß-) proteins associated with dystrophin. Ibraghimov-Beskrovnaya., who suggested the name "dystroglycan" (dystrophin-associted glycoprotein), .... Smalheiser & Schwartz.... showed that both proteins are encoded by a single chromosome 3p21-derived 5.8 kb transcript. Mature alpha- and ß-dystroglycan are derived from this transcript by post-translational processing of the encoded 97 kD precursor protein. ß-Dystroglycan contains a single transmembrane domain, three potential N-linked glycosylation sites and a cytoplasmic tail. alpha-Dystroglycan contains no transmembrane domain, one potential N-linked and numerous O-linked glycosylation sites.
No human disease has yet been linked to dystroglycan mutations. Mice homozygously lacking dystroglycan show embryonic lethality, thought to arise from defects in extra-embryonic structures and their association with the extra-cellular matrix (Williamson).
Ibraghimov-Beskrovnaya et al. first reported the cloning of dystroglycan after screening of a rabbit skeletal muscle cDNA expression library with a polyclonal antibody raised against ß-dystroglycan (43 kDa DAG). The human ß-dystroglycan gene, designated DAG1, was cloned and characterized by Ibraghimov-Beskrovnaya et al. The coding region of the gene is split over one small and one large (2.4 kb) exon, the 5'- and 3'-untranslated regions over 2 or more exons. The chromosomal localization, determined by using somatic cell hybrids and FISH, was 3p21.1-21.31. This region is syntenic with mouse chromosome 9.
| Exon | Exon size (bp) | Intron size (kb) | 5' cDNA position | Splice after | Remarks |
|---|---|---|---|---|---|
| 1 | ? | >10 | ? | - | 5'UTR |
| 2 | >285 | >6 | ? | 0 | 5'UTR / 285 bp coding |
| 3 | 2,400 | <3 | 286 | - | 2400 bp coding / 3'UTR; TMR, N-Glyco Asn-641, -649, -661 |
| 4.. | ? | ? | - | - | 3'UTR |
Legend:
Exon: numbering of exons and intron/exon boundaries are according to Ibraghimov-Beskrovnaya, with the first base of the Met-codon
counted as position 1 (see Reference sequence). Exon size: size of exon indicated
in basepairs. Intron size: size of intron indicated in kilobasepairs. 5' cDNA
position: first base of the exon (according to cDNA sequence Ibraghimov-Beskrovnaya).
Splice after: splicing occurs in between of two coding triplets (0), after the
first (1) or the second (2) base of a triplet. Remarks: 5'UTR = 5' untranslated
region, 3'UTR = 3' untranslated region, N-Glyco = potential N-linked glycosylation site,
Phos = putative phosphorylation site, TMR = transmembrane region.
None reported yet.
On Northern blots, a dystroglycan transcript of 5,8 kb could be detected in fetal and adult cardiac muscle, brain, kidney, liver and lung and in adult diaphragm, placenta, pancreas, skeletal muscle and stomach (Ibraghimov-Beskrovnaya, Ibraghimov-Beskrovnaya). Expression is most abundant in muscle and heart.
None reported yet.
Dystroglycan, for dystrophin-associted glycoprotein (Ibraghimov-Beskrovnaya), is an integral membrane glycoprotein localized to the sarcolemma of skeletal muscle. Dystroglycan mRNA contains a 895 amino acid open reading frame encoding a precursor protein with a calculated molecular weigth of 97,552 daltons (Ibraghimov-Beskrovnaya). The first 27 amino acids of the precursor are predominantly hydrophobic and probably represent a signal peptide. Post-translational processing of the 97 kD precursor, probably through cleavage at Arg-457, ultimately yields the two mature proteins alpha-dystroglycan (C-terminal half) and ß-dystroglycan (N-terminal half). The exact cleavage point could not be determined because the N-terminus of alpha-dystrocglycan is blocked.
On Western blot, 43 kD beta-dystroglycan was found in membranes from skeletal and cardiac muscle, brain and lung. 156 kD alpha-Dystroglycan was found in skeletal muscle membranes, with a slightly lower Mr in cardiac muscle membranes and as a ~120 kD protein in brain and lung membranes (the size differences probably originate from differential glycosylation).
Human and rabbit dystroglycan show a 93% amino acid identity, while 90% of the amino acid changes are conservative.
No human disease has yet been linked to dystroglycan mutations. Mice homozygously lacking dystroglycan show embryonic lethality, thought to arise from defects in extra-embryonic structures and their association with the extra-cellular matrix (Williamson).
Although dystroglycan mRNA levels in DMD-patients and mdx-mouse muscle are normal, alpha- and ß-dystroglycan protein are drastically reduced. On the contrary, alpha-dystroglycan protein is normal in brain and kidney membranes of mdx-mice.
None reported yet.
None reported yet.
None reported yet.
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