Disease relevance of Ds

• Although other mouse mutations produce similar congenital defects, extreme pleiotropism, random occurrence, developmental independence of multiple defects, and type of anomaly make Ds unique [1].
• Here, we show that Runx1 is required to sustain muscle by preventing denervated myofibers from undergoing myofibrillar disorganization and autophagy, structural defects found in a variety of congenital myopathies [2].
• Islet disorganization and fibrosis did not result from lymphocytic infiltration, since they were also observed in SCID mice bearing the transgene [3].
• We report the generation of Cd151-null mice that recapitulate the renal pathology of human patients, i.e., with age they develop massive proteinuria caused by focal glomerulosclerosis, disorganization of the glomerular basement membrane, and tubular cystic dilation [4].
• Normoleptinemic control ACS-transgenic mice developed severe dilated cardiomyopathy with thickened left ventricular walls and profound impairment of systolic function on echocardiogram; histologically, there was severe myofiber disorganization and interstitial fibrosis, with intracytoplasmic lipid vacuoles identifiable by electron microscope [5].

Psychiatry related information on Ds

• Centrosome disorganization in fibroblast cultures derived from R6/2 Huntington's disease (HD) transgenic mice and HD patients [6].
• The histopathological features of eye disease in hamsters were different from those in rats and were characterized by microophthalmia (especially in runted hamsters) and abnormal proliferation, disorientation, and disorganization of corneal, lens, and retinal tissues [7].

High impact information on Ds

• Overexpression of the nonphosphorylatable mutant FAK S732A results in disorganization of the microtubule fork and impairment of nuclear movement in vitro, and neuronal positioning defects in vivo [8].
• In an accompanying paper, it is shown that mutations in the mouse ortholog cause disorganization of inner ear stereocilia and deafness in the waltzer mouse [9].
• Hspg2-/- cartilage showed severe disorganization of the columnar structures of chondrocytes and defective endochondral ossification [10].
• Mice with further reduction of Pafah1b1 activity display more severe brain disorganization as well as cerebellar defects [11].
• Electron microscopic analysis of the heart revealed disorganization of myofibrils and disruption of Z-disks [12].

Chemical compound and disease context of Ds

• In murine erythroleukemia cells, brefeldin A caused a rapid and extensive disorganization of the entire Golgi complex accompanied by the accumulation of membranes in a part of the ER closely associated with ER transitional elements [13].
• They also reinforce in vivo the importance of activated Neu in causing disorganization of mammary luminal epithelial cell junctions and provide support for an invasion-independent mechanism of metastasis [14].
• In step 5 (72 to 96 h), severe airspace disorganization, lipid peroxidation (high malondialdehyde release in BAL fluid), and diffuse tissue damage coincided with high NO levels; there was further increase in lung weight and bacterial growth, loss in body weight, and high mortality rate [15].
• Altogether, our results suggest that impairment of oxidative metabolism, followed by mitochondrial swelling and disorganization of cristae, is the main cause of cell mortality in severely thiamine-deficient neuroblastoma cells [16].
• Untreated ACS-transgenic mice died prematurely with increased triacylglycerol content and dilated cardiomyopathy, impaired systolic function and myofiber disorganization, apoptosis, and interstitial fibrosis on microscopy [17].

Biological context of Ds

• This mapping assignment places the Gata4 gene in the vicinity of the mouse Ds (disorganization) locus, a dominant gain-of-function mutation affecting embryonic development [18].
• Ds may therefore serve not only as a model for developmental anomalies in cell fate and pattern formation but also for complex developmental traits showing variable expressivity, low penetrance, and sporadic occurrence in mice and humans [19].
• To characterize the effects of gene dosage, we examined the viability and phenotype of Ds homozygotes and the phenotype of +/+/Ds trisomic fetuses [1].
• Not only were Ds homozygotes found in their expected frequency, homozygotes were not more severely affected than heterozygotes [1].
• Trisomies provide a direct test for determining whether Ds is a gain-of-function mutation [1].

Anatomical context of Ds

• Two trisomic fetuses had developmental defects characteristic of Ds mice [1].
• Rho+/- animals retain the majority of their photoreceptors although the inner and outer segments of these cells display some structural disorganization, the outer segments becoming shorter in older mice [20].
• Most mice lacking Mef2a died suddenly within the first week of life and exhibited pronounced dilation of the right ventricle, myofibrillar fragmentation, mitochondrial disorganization and activation of a fetal cardiac gene program [21].
• Null mice display ataxia, behavioral abnormalities, and tremors that correlate with a twofold decrease in brain mass that disproportionately affects the cerebellum (sixfold reduced in mass) and the cerebral cortex, both of which show signs of disorganization [22].
• Runx1 prevents wasting, myofibrillar disorganization, and autophagy of skeletal muscle [2].

Associations of Ds with chemical compounds

• Mannose exposure caused reduction in kidney size and disorganization of ureteric bud branches with inhibition of glomerulogenesis [23].
• Rhodaminephalloidin labeling of actin filaments revealed a field-induced disorganization of the stress fiber pattern, which was reduced when stimulation was conducted in calcium-depleted buffer or in buffer containing calcium antagonist CoCl2, calcium channel blocker D-600, or calmodulin antagonist trifluoperazine [24].
• 3-Deazaadenosine-induced disorganization of macrophage microfilaments [25].
• When cells were treated with brefeldin A (BFA) or nocodazole, drugs that promote Golgi disorganization, we observed STK16 translocation to the nuclear compartment [26].
• Thus, progressive T-tubule disorganization during CHF promotes dyssynchrony of SR Ca(2+) release which may contribute to the slowing of SR Ca(2+) release in this condition [27].

Physical interactions of Ds

• The absence of dystrophin complex leads to disorganization of the force-transmitting costameric cytoskeleton and disruption of sarcolemmal membrane integrity in skeletal muscle [28].

Regulatory relationships of Ds

• Consistent with this, Omomyc reverses Myc-induced cytoskeletal disorganization in C2C12 myoblasts [29].
• Targeted inactivation of the neuropilin-1 gene in mice induced disorganization of the pathway and projection of nerve fibers, suggesting that neuropilin-1 mediates semaphorin-elicited signals and regulates nerve fiber guidance in embryogenesis [30].
• Stimulus-dependent disorganization of actin filaments induced by overexpression of cofilin in C2 myoblasts [31].

Other interactions of Ds

• Unlike the two-hit model that has been used to describe the development of retinoblastoma, the "second hit" for Ds is thought not to arise in the other Ds allele [32].
• Although the tensile properties of the wounds were unchanged, ultrastructural analysis showed a significantly decreased level of debridement, greater disorganization of matrix, and an alteration of collagen fibrillogenesis leading to small diameter collagen fibrils in the OPN mutant mice [33].
• Cystic embryoid bodies derived from afadin(-/-) embryonic stem cells showed normal organization of the endoderm but disorganization of the ectoderm [34].
• However, after this time, marked disorganization of the vascular system was observed in those chimeric mice that have a high contribution of Lmo2-null ES cells [35].
• In this model, Capn3 proteolytic activity leads to disruption of the actin cytoskeleton and disorganization of focal adhesions through cleavage of several endogenous proteins [36].

Analytical, diagnostic and therapeutic context of Ds

• In addition, scanning electron microscopy revealed advanced changes of cell surfaces with reduction of microvilli and disorganization of cytoarchitecture [37].
• Histologic examination revealed disorganization of the vascular endothelium and its surrounding structures, and immunohistochemistry demonstrated disturbances in vascular formation and colonization of immature hematopoietic cells [38].
• 5. Histological examinations and in situ hybridization reveal disorganization of columnar epithelium and the presence of hematomas within the neuroepithelium and disruption of the basement membrane lying between this and mesenchymal tissues, both of which express Fli1 at the time of hemorrhaging [39].
• Correlated video and electron microscopy suggested that the mechanism of arrest by antiastrotactin antibodies involved the failure to form new adhesion sites along the leading process and the disorganization of cytoskeletal components [40].
• Immunofluorescence revealed that disorganization of the ameloblast layer was associated with a loss of laminin-5, an extracellular matrix molecule mediating epithelial anchorage [41].

References