Disease relevance of DAG1

• Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy [1].
• These results support the hypothesis that the dramatic reduction in the 156K DAG in Duchenne muscular dystrophy leads to a loss of a linkage between the sarcolemma and extracellular matrix and that this may render muscle fibres more susceptible to necrosis [2].
• Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, delta-sarcoglycan, in hamster: an animal model of disrupted dystrophin-associated glycoprotein complex [3].
• The observed loss of laminin-111 assembly and signaling in Dag1(-/-) mammary epithelial cells provides insights into the signaling changes occurring in breast carcinomas and other cancers, where the binding function of DG to laminin is frequently defective [4].
• In the ischemic core (infarction), DAG concentration increased slowly, and its peak concentration was lower than that in normal tissue [5].

High impact information on DAG1

• Brief report: deficiency of a dystrophin-associated glycoprotein (adhalin) in a patient with muscular dystrophy and cardiomyopathy [6].
• Marked deficiency of muscle adhalin, a 50 kDa sarcolemmal dystrophin-associated glycoprotein, has been reported in severe childhood autosomal recessive muscular dystrophy (SCARMD) [7].
• Here we report the specific deficiency of the 50K dystrophin-associated glycoprotein (M(r) 50,000) in sarcolemma of SCARMD patients [1].
• Thus, the 156K DAG is a new laminin-binding glycoprotein which may provide a linkage between the sarcolemma and extracellular matrix [2].
• Here, it is shown that a mutation in the gene encoding the 35-kilodalton dystrophin-associated glycoprotein, gamma-sarcoglycan, is likely to be the primary genetic defect in this disorder [8].

Biological context of DAG1

• The human dystroglycan is encoded by a single gene (DAG1) mapped to chromosome 3 band p21 [9].
• However, no direct correlation between DAG1 SNPs and clinical severity of HIBM could be detected [10].
• These data are valuable for future studies on the role of DAG1 in HIBM and other muscular dystrophies, especially those dystrophies that involve abnormal glycosylation of dystroglycan [10].
• E-cadherin and DAG1 gene expression levels were measured using real-time PCR [11].
• Previous work from our laboratory demonstrated that 1,25(OH)2D3 rapidly stimulated hydrolysis of membrane polyphosphoinositides (PI) in rat colonocytes and in Caco-2 cells, generating the second messengers DAG and IP3 [12].

Anatomical context of DAG1

• Dystrophin and the dystrophin-associated glycoprotein, beta-dystroglycan, co-localize in photoreceptor synaptic complexes of the human retina [13].
• Importantly, the accumulation of beta-dystroglycan along the membranes of vector-treated DMD myotubes indicated proper assembly of dystrophin-associated glycoprotein complexes [14].
• The antibody specifically reacted with A3a of rabbit skeletal muscle [15].
• The sarcoglycans are components of the dystrophin-associated glycoprotein (DAG) complex which forms a mechanical link between the intracellular cytoskeleton and extracellular matrix [16].
• DAG increments were most pronounced (approximately 360% of basal levels) when cells were preincubated with [14C]lysophosphatidylcholine, which was predominantly incorporated into the phosphatidylcholine (PC) pool of the plasma-membranes [17].

Associations of DAG1 with chemical compounds

• The potential energy surfaces of the three different positional isomers of diaminoguanidine (DAG1, DAG2, and DAG3) have been studied in detail, which suggest greater stability for DAG1 over the other isomers [18].
• Preliminary studies have shown that 1,25(OH)2D3 also activated phosphatidylcholine phospholipase D (PLD) in Caco-2 cells, generating phosphatidic acid and contributing to the sustained rise in DAG [12].
• Further extensive examination of changes in metabolically labeled phospholipids indicated that TNF-stimulated hydrolysis of PC is accompanied by the generation of phosphorylcholine and DAG [17].
• Exogenous phospholipase C (which releases DAG and inositol 1,4,5-triphosphate), PKC activators (phorbol esters and DAG), Ca2+ ionophores, and a cyclic AMP analog all transiently induced accumulation of LDL-R mRNA [19].
• Whereas much attention has been devoted to inositol trisphosphate (IP3) production and intracellular Ca2+ release, little is known about the possible role of the DAG branch in the generation of the light response [20].

Physical interactions of DAG1

• Agrin binds to a second protein complex on the muscle surface known as the dystrophin-associated glycoprotein complex [21].

Other interactions of DAG1

• The laminin-binding 156DAG and 43DAG are encoded by a single gene and are now called alpha- and beta-dystroglycan, respectively [22].
• Muscle immunohistochemistry revealed normal dystrophin I and II staining but complete absence for adhalin, a dystrophin associated glycoprotein [23].
• Absence of gamma-sarcoglycan (35 DAG) in autosomal recessive muscular dystrophy linked to chromosome 13q12 [24].
• The most active compound (3c) inhibited the proliferation, induced apoptosis, and decreased the expression of p-Stat5 and p-Pyk2 in DAG-1 and RT112 lines in which the FGFR3 is either mutated or overexpressed [25].
• CONCLUSION: The DAG-1 cell line is a useful tool, both in vitro and in vivo, to study the progression of bladder tumors and their mechanisms of resistance to immunotherapy in relation with PAI-2 and antioxidant enzymes [26].

Analytical, diagnostic and therapeutic context of DAG1

• Single base polymorphism in the DAG1 gene detected by DGGE and mismatch PCR [27].
• For the measurement of phosphoinositide turnover after intravenous injection of DAG, dynamic PET data were collected continuously for 46 min [5].
• Polymerase chain reaction and northern blot analysis have shown both H. armigera A3a and A3b genes are expressed during pupal development and in the brain of newly enclosed adults [28].
• In comparison with the control groups, all biomaterials (PLLA, PGPD, and collagen I/III) showed a significant increase in local Ca(2+) accumulation under DAG stimulation after 28 days in vitro [29].
• Concomitantly, the significant enhancement of the level of DAG and AA radioactivity at this short reperfusion time confirmed the active PI degradation by phospholipase(s) in cerebral cortex and hippocampus [30].

References