Disease relevance of Alternative Splicing

• Here we show that expression of a human equivalent to Drosophila's C4 pol II in human cultured cells affects alternative splicing of the fibronectin EDI exon and adenovirus E1a pre-mRNA [1].
• Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing [2].
• Our results demonstrate that transcripts encoding agrin proteins with high AChR aggregating activity are expressed exclusively by neurons in the ciliary ganglion and that alternative splicing of agrin mRNA is regulated during development and in a cell-specific manner [3].
• Quantitative reverse transcriptase-PCR of the wild-type (C) tyrosinase gene in transgenic (C57BL/6 strain) mouse melanomas has revealed a shift toward alternative splicing of the pre-mRNA that generated increased levels of the Delta1b and Delta1d mRNA splice variants [4].
• Normally, by alternative splicing, this 118-nucleotide R element represents the most 5' region of several HTLV-I transcripts including tax, rex, and env [5].

Psychiatry related information on Alternative Splicing

• Levels and alternative splicing of amyloid beta protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer's disease [6].
• Exogenous Id, a negative regulator of MyoD, blocked muscle-specific alternative splicing of F1gamma pre-mRNA by both types of induction [7].
• At least two different kinds of IGF-I that are expressed by skeletal muscle are derived from the IGF-I gene by alternative splicing, one of which is expressed in response to physical activity which has now been called 'mechano growth factor' (MGF) [8].
• Interesting phenotype-genotype correlations have resulted from the recognition of large-scale deletions in MECP2 as a cause of Rett syndrome, and the more recent identification of an alternate splicing isoform of the gene product [9].

High impact information on Alternative Splicing

• Recent work has focused on regulation of CD45 expression and alternative splicing, isoform-specific differences in signal transduction, and regulation of phosphatase activity [10].
• The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events [11].
• The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation [12].
• Alternative splicing of Dscam generates an enormous molecular diversity with maximally 38,016 different receptors [13].
• Genome-wide quantitative analysis of alternative splicing using a custom Affymetrix microarray indicate that the neuronal splicing factor Nova2 regulates a biologically coherent set of transcripts encoding synaptic proteins [14].
• Nova1 and Nova2 regulate alternative splicing of ~700 brain transcripts by directly binding to clusters of YCAY elements. [15]
• The position at which the Nova1 and Nova2 proteins bind a pre-mRNA dictate the outcome of alternative splice site selection. [16]

Chemical compound and disease context of Alternative Splicing

• Glanzmann's thrombasthenia associated with deletion-insertion and alternative splicing in the glycoprotein IIb gene [17].
• De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1 [18].
• Pancreatic islets and insulinoma cells express a novel isoform of group VIA phospholipase A2 (iPLA2 beta) that participates in glucose-stimulated insulin secretion and is not produced by alternate splicing of the iPLA2 beta transcript [19].
• Extensive alternative splicing of NEB may explain why nemaline myopathy patients with homozygous truncating mutations show expression of the carboxy-terminus of the nebulin protein contrary to expectations [20].
• The human peripheral benzodiazepine receptor gene: cloning and characterization of alternative splicing in normal tissues and in a patient with congenital lipoid adrenal hyperplasia [21].

Biological context of Alternative Splicing

• Drosophila Dscam encodes 38,016 distinct axon guidance receptors through the mutually exclusive alternative splicing of 95 variable exons [22].
• SR proteins serve multiple roles in the posttranscriptional control of gene expression, including as regulators of alternative splicing [23].
• We also present evidence for alternative splicing of the FMR-1 gene in mouse and human brain and show that one of these splicing events alters the FMR-1 reading frame, predicting isoforms with novel carboxy termini [24].
• These results support a model in which increased expression of a splicing regulator contributes to insulin resistance in DM1 by affecting IR alternative splicing [25].
• DNA sequence data indicate that bcl-2 encodes two proteins by virtue of alternative splicing, designated as Bcl-2 alpha and Bcl-2 beta, with relative molecular masses of 26,000 and 22,000 respectively [26].
• The Nova2 neuron-specific alternative splicing factor regulates cortical neuronal migration by regulating splicing of disabled-1. [27]
• Nova1 is a neuron-specific regulator of alternative splicing and is essential for motor neuron viability. [28]

Anatomical context of Alternative Splicing

• Here we demonstrate that alternative splicing of the insulin receptor (IR) pre-mRNA is aberrantly regulated in DM1 skeletal muscle tissue, resulting in predominant expression of the lower-signaling nonmuscle isoform (IR-A) [25].
• We conclude that the four forms of this myelin protein are encoded in separate mRNAs, each derived by a simple alternative splicing of the primary MBP gene transcript [29].
• ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle [30].
• Alternative splicing of the sex determination gene transformer-2 is sex-specific in the germ line but not in the soma [31].
• Our results not only demonstrate the biological significance of alternative splicing in the immune system, but also suggest a model for regulating RPTP dimerization and function [32].

Associations of Alternative Splicing with chemical compounds

• The transmembrane tyrosine phosphatase CD45 is expressed in multiple isoforms on all nucleated hematopoietic cells, resulting from alternative splicing of variable exons [33].
• Developmentally regulated alternative splicing of Drosophila integrin PS2 alpha transcripts [34].
• A second alternative splicing event generates two additional receptor isoforms that lack a proline cluster in the external juxtamembrane region and have lower affinity for activin A [35].
• Alternative splicing directs the expression of two D2 dopamine receptor isoforms [36].
• Alternative splicing of C-terminal tail of prostaglandin E receptor subtype EP3 determines G-protein specificity [37].

Gene context of Alternative Splicing

• These structures provide a molecular basis for FGF1 as a universal FGFR ligand and for modulation of FGF-FGFR specificity through primary sequence variations and alternative splicing [38].
• These results demonstrate that both protein-RNA and protein-protein interactions are involved in tra2-dependent activation and repression of alternative splicing [39].
• Alternative splicing of Drosophila Dscam generates axon guidance receptors that exhibit isoform-specific homophilic binding [40].
• Furthermore, the para transcript appears to undergo alternative splicing to produce several distinct subtypes of this channel [41].
• Thus, alternative splicing of NF2 may regulate betaII-spectrin binding [42].

Analytical, diagnostic and therapeutic context of Alternative Splicing

• In situ hybridization reveals that alternative splicing of neurexins at the site recognized by neuroligin 1 is highly regulated [43].
• Sequence analysis of otu cDNAs suggests that these proteins are translated from two mRNAs generated by alternative splicing of a 126-bp exon between the sixth and seventh exon of the smaller transcript [44].
• Sequencing of genomic DNA amplified by the polymerase chain reaction (PCR) revealed that the extra sequence was derived from the 3'-end of intron 7 by alternative splicing [45].
• We have established mice selectively lacking CD3 zeta but able to express CD3 eta, a polypeptide produced from the same locus through alternative splicing, using the method of gene targeting in embryonic stem cells [46].
• Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails [47].

References