Alternative RNA Splicing

Fast skeletal troponin T gene and spliced mRNAs 

Any of the 32 possible combinations with zero, one, two, three, four, or all five of exons 4 through 8 

After being transcribed from DNA, many RNA molecules are modified, often extensively, before they arrive at their final form. 

Several modifications are common with tRNA and rRNA, such as trimming, addition of terminal sequences, and base modification. 

Messenger RNA is also modified by the removal of intervening sequences, or introns. 

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N10. Noguchi, T., Inoue, H., and Tanaka, T., The M,- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. J. Biol. Chem. 261,13807-13812 (1986). 

Chung, D. W., and Davie, E. W. (1984). Gamma and gamma chains of human fibrinogen are produced by alternative RNA splicing. Biochem. 23, 4232-4236. 

Bracco L, Kearsey J. The relevance of alternative RNA splicing to pharmaco-genomies. Trends Biotechnol 2003 21 346-353. 

Fig. 8. Alternative RNA splicing pathways. In the simple example shown, the transcript can be spliced by alternative pathways leading to two mRNAs with different coding capacities, i.e. exons 1, 2 and 3 or just exons 1 and 3. For genes containing many exons, a substantial number of alternative splice pathways may exist which are...

Monsma FJ, Jr, McVittie LD, Gerfen CR, Mahan LC, Sibley DR (1989) Multiple D2 dopamine receptors produced by alternative RNA splicing. Nature 342 926-929. 

Patel, B. N., Dunn, R. J., and David, S. (2000). Alternative RNA splicing generates a glycosylphosphatidylinositol-anchored form of ceruloplasmin in mammalian brain. /. Biol. Chem. 275, 4305-4310. 

D Souza I, Poorkaj P, Hong M, NocUin D, Lee VM et si (1999) Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Nad Acad Sci USA 96 5598-5603... 

Table 28.4. Selected proteins exhibiting alternative RNA splicing...

Zhang, K., Saxon, A. and Max, E.E. (1992). Two unusual forms of human immunoglobulin E encoded by alternative RNA splicing of epsilon heavy chain membrane exons. J. Exp. Med. 176, 233-243. 

Zhang, K., Max, E.E., Cheah, H.K. and Saxon, A. (1994a). Complex alternative RNA splicing of epsilon-immunoglobulin transcripts produces mRNAs encoding four potential secreted protein isoforms. J. Biol. Chem. 269, 456-462. 

Nawa, H., Kotani, H. and Nakanishi, S. (1984). Tissue-specific generation of two pteptotachykinin mRNAs from one gene by alternative RNA splicing. Nature 312, 729-734. 

Monsma, J., F.J. McVittie, L.D. Gerfen, C.R. Mahan, L.C. Sibley, D.R. (1989) Multiple D2 dopamine receptors produced by alternative RNA splicing. Nature 342, 926-929. O Malley, K.L. Mack, K.J. Gandelman, K.Y. Todd, K.D. (1990) Organization and expression of the rat D2A receptor gene identification of alternative transcripts and a variant donor splice site. Biochemistry 29, 1367-1371. 

Similarly, multiple genes, alternative RNA splicing, and posttranslational modifications result in multiple essential and regulatory light chains, tropomyosins, titins, and other myofibrillar proteins. Energy pathway enzymes are differentially expressed in various skeletal fiber types, in cardiac and smooth muscle, and at different stages of development. This also applies to Ca regulatory proteins such as the... 

Fig. 6. Structures of desmosomal cadherins. Nomenclature from Buxton et al. [48]. For explanation of symbols see Fig. 2. Dsc3a and Dsc3b are the products of alternative RNA splicing of the DSC3 gene see text for details.

N-CAM is encoded by a single gene that gives rise to a large number of isoforms by alternative RNA splicing and by post-translation modifications including unique patterns of glycosylation [60]. The three major forms (Fig. 7) are similar in their extracellular... 

Alternative RNA Splicing Increases the Number of Proteins Expressed from a Single Eukaryotic Gene... 

Isolated from various tissues and comparison of their sequences with genomic DNA has revealed that nearly 60 percent of all human genes are expressed as alternatively spliced mRNAs. Clearly, alternative RNA splicing greatly expands the number of proteins encoded by the genomes of higher, multicellular organisms. 

The primary CAMs in adherens junctions and desmosomes belong to the cadherin family. In vertebrates and invertebrates, this protein family of more than 100 members can be grouped into at least six subfamilies. The diversity of cadherins arises from the presence of multiple cadherin genes and alternative RNA splicing, which generates multiple mRNAs from one gene. 

Two types of soluble binding protein have been described, nonspecific serum proteins and cytokine-specific soluble receptor proteins. The major nonspecific serum protein capable of binding cytokines appears to be a2-macroglobuIin (B57, B58, Mil). A number of soluble cytokine inhibitors related to the relevant receptor have been described. The soluble form of the IL-2R a chain has been found in the serum of apparently normal individuals and is increased in the serum of individuals with inflammatory diseases such as rheumatoid arthritis (W31). Similar molecules have been described for IL-1, IL-6, IFNy, and IL-7 (F7, N14, S62). The mechanism of release has not been properly established but appears to require proteolytic cleavage of the membrane-bound receptor. Soluble inhibitors for two other cytokines, IL-4 and TNF, appear to be derived by alternative RNA splicing sites that give rise to receptors lacking a transmembrane sequence and that are secreted (M50, S22). 

Eukaryotic mRNAs contain a 507-methylguanosine cap and a 30 polyadenylate tail, both of which are added by specific enzymes localized to the nucleus. Alternative RNA splicing and polyadenylation contribute to transcript heterogeneity and specificity, and can result in the synthesis of cell-specific proteins. 

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