Defects in pre-mRNA processing as causes of and predisposition to diseases.

Humans possess a surprisingly low number of genes and intensively use pre-mRNA splicing to achieve the high molecular complexity needed to sustain normal body functions and facilitate responses to altered conditions. Because hundreds of thousands of proteins are generated by 25,000 to 40,000 genes, pre-mRNA processing events are highly important for the regulation of human gene expression. Both inherited and acquired defects in pre-mRNA processing are increasingly recognized as causes of human diseases, and almost all pre-mRNA processing events are controlled by a combination of protein factors. This makes defects in these processes likely candidates for causes of diseases with complicated inheritance patterns that affect seemingly unrelated functions. The elucidation of genetic mechanisms regulating pre-mRNA processing, combined with the development of drugs targeted at consensus RNA sequences and/or corresponding proteins, can lead to novel diagnostic and therapeutic approaches.

[1]  G. Dreyfuss,et al.  Messenger-RNA-binding proteins and the messages they carry , 2002, Nature Reviews Molecular Cell Biology.

[2]  J. Steitz,et al.  Pre-mRNA splicing: the discovery of a new spliceosome doubles the challenge. , 1997, Trends in biochemical sciences.

[3]  R. Willemze,et al.  High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia. , 2000, Blood.

[4]  Patrick J. Paddison,et al.  Stable suppression of gene expression by RNAi in mammalian cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[5]  H. Soreq,et al.  Acetylcholinesterase — new roles for an old actor , 2001, Nature Reviews Neuroscience.

[6]  M. Mattei,et al.  Structure and Expression of the ATFa Gene* , 1996, The Journal of Biological Chemistry.

[7]  G. Neri,et al.  Detection of the survival motor neuron (SMN) genes by FISH: further evidence for a role for SMN2 in the modulation of disease severity in SMA patients. , 1999, Human molecular genetics.

[8]  H. Dietz,et al.  Nonsense-mediated mRNA decay in health and disease. , 1999, Human molecular genetics.

[9]  E G Jones,et al.  Altered ratios of alternatively spliced long and short gamma2 subunit mRNAs of the gamma-amino butyrate type A receptor in prefrontal cortex of schizophrenics. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[10]  P. Schofield,et al.  Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations. , 2000, Brain : a journal of neurology.

[11]  H. Dietz,et al.  Glanzmann thrombasthenia. Cooperation between sequence variants in cis during splice site selection. , 1996, The Journal of clinical investigation.

[12]  S. Hilsenbeck,et al.  Multiple splicing variants of the estrogen receptor are present in individual human breast tumors , 1996, The Journal of Steroid Biochemistry and Molecular Biology.

[13]  James I. Garrels,et al.  Annotating the human proteome: the Human Proteome Survey Database (HumanPSDTM) and an in-depth target database for G protein-coupled receptors (GPCR-PDTM) from Incyte Genomics , 2002, Nucleic Acids Res..

[14]  L. Timchenko,et al.  Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy. , 1999, Human molecular genetics.

[15]  F. Kittrell,et al.  Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis , 1999, Oncogene.

[16]  L. Minvielle-Sebastia,et al.  mRNA polyadenylation and its coupling to other RNA processing reactions and to transcription. , 1999, Current opinion in cell biology.

[17]  S. Stamm,et al.  Ischemia Induces a Translocation of the Splicing Factor tra2-β1 and Changes Alternative Splicing Patterns in the Brain , 2002, The Journal of Neuroscience.

[18]  G. Tiscornia,et al.  Myotonic dystrophy: the role of the CUG triplet repeats in splicing of a novel DMPK exon and altered cytoplasmic DMPK mRNA isoform ratios. , 2000, Molecular cell.

[19]  S. Riva,et al.  The roles of heterogeneous nuclear ribonucleoproteins (hnRNP) in RNA metabolism , 1996, BioEssays : news and reviews in molecular, cellular and developmental biology.

[20]  D. Black,et al.  Alternative RNA splicing in the nervous system , 2001, Progress in Neurobiology.

[21]  Brenton R Graveley,et al.  Exon-specific RNAi: a tool for dissecting the functional relevance of alternative splicing. , 2002, RNA.

[22]  P. Harrison,et al.  Acute intermittent porphyria caused by defective splicing of porphobilinogen deaminase RNA: a synonymous codon mutation at -22 bp from the 5' splice site causes skipping of exon 3. , 1996, Journal of medical genetics.

[23]  Gil Ast,et al.  How did alternative splicing evolve? , 2004, Nature Reviews Genetics.

[24]  A. Wolffe,et al.  A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2. , 1998, Molecular cell.

[25]  P. Herrlich,et al.  Regulation of alternative pre‐mRNA splicing by the ERK MAP‐kinase pathway , 2001, The EMBO journal.

[26]  R. Sperling,et al.  RNA editing activity is associated with splicing factors in lnRNP particles: The nuclear pre-mRNA processing machinery , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Swanson,et al.  hnRNP complexes: composition, structure, and function. , 1999, Current opinion in cell biology.

[28]  D. Dickson,et al.  Tau gene mutation in familial progressive subcortical gliosis , 1999, Nature Medicine.

[29]  T. Dörk,et al.  Nuclear factor TDP‐43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping , 2001, The EMBO journal.

[30]  J. Mendell,et al.  When the Message Goes Awry Disease-Producing Mutations that Influence mRNA Content and Performance , 2001, Cell.

[31]  Sharlene R. Lim,et al.  Modulation of Survival Motor Neuron Pre-mRNA Splicing by Inhibition of Alternative 3′ Splice Site Pairing* , 2001, The Journal of Biological Chemistry.

[32]  K. Weinberg,et al.  Three new adenosine deaminase mutations that define a splicing enhancer and cause severe and partial phenotypes: implications for evolution of a CpG hotspot and expression of a transduced ADA cDNA. , 1995, Human molecular genetics.

[33]  C. Thompson,et al.  bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death , 1993, Cell.

[34]  A. Krainer,et al.  Serine Phosphorylation of SR Proteins Is Required for Their Recruitment to Sites of Transcription In Vivo , 1998, The Journal of cell biology.

[35]  B. Sullenger,et al.  Induction of wild-type p53 activity in human cancer cells by ribozymes that repair mutant p53 transcripts. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. Stamm,et al.  Complex Regulation of Tau Exon 10, Whose Missplicing Causes Frontotemporal Dementia , 2000, Journal of neurochemistry.

[37]  U. Francke,et al.  Silent mutation induces exon skipping of fibrillin-1 gene in Marfan syndrome , 1997, Nature Genetics.

[38]  P. Grabowski.  Splicing Regulation in Neurons: Tinkering with Cell-Specific Control , 1998, Cell.

[39]  G. Neri,et al.  Premature termination mutations in exon 3 of the SMN1 gene are associated with exon skipping and a relatively mild SMA phenotype , 2001, European Journal of Human Genetics.

[40]  J. Taylor,et al.  Apolipoprotein B mRNA-editing protein induces hepatocellular carcinoma and dysplasia in transgenic animals. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S. Packman,et al.  Diverse mutations in patients with Menkes disease often lead to exon skipping. , 1994, American journal of human genetics.

[42]  T. Dawson,et al.  Regulation of alternative splicing by RNA editing , 1999, Nature.

[43]  D. Bentley,et al.  Coupling RNA polymerase II transcription with pre-mRNA processing. , 1999, Current opinion in cell biology.

[44]  R J Wyatt,et al.  Elevated concentration of N-CAM VASE isoforms in schizophrenia. , 2000, Journal of psychiatric research.

[45]  G. Schellenberg,et al.  Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  T. Giordano,et al.  RNA as a drug target: methods for biophysical characterization and screening. , 2000, Trends in biotechnology.

[47]  M G Spillantini,et al.  Structural basis for recognition of the RNA major groove in the tau exon 10 splicing regulatory element by aminoglycoside antibiotics. , 2000, Nucleic acids research.

[48]  G. Mortier,et al.  Characterisation of two different nonsense mutations, C6792A and C6792G, causing skipping of exon 37 in the NF1 gene , 1997, Human Genetics.

[49]  S. Orkin,et al.  Thalassemia due to a mutation in the cleavage‐polyadenylation signal of the human beta‐globin gene. , 1985, The EMBO journal.

[50]  F. Couch,et al.  Mutations and Polymorphisms in the familial early‐onset breast cancer (BRCA1) gene , 1996, Human mutation.

[51]  G. Schellenberg,et al.  Determinants of 4-Repeat Tau Expression , 2000, The Journal of Biological Chemistry.

[52]  J. Yong,et al.  The Y14 protein communicates to the cytoplasm the position of exon–exon junctions , 2001, The EMBO journal.

[53]  M. Gerstein,et al.  A question of size: the eukaryotic proteome and the problems in defining it. , 2002, Nucleic acids research.

[54]  G. Schellenberg,et al.  A distinct familial presenile dementia with a novel missense mutation in the tau gene. , 1999, Neuroreport.

[55]  J. Manley,et al.  Determinants of SR protein specificity. , 1999, Current opinion in cell biology.

[56]  M. Sowden,et al.  Regulation of hepatic apolipoprotein B RNA editing in the genetically obese Zucker rat. , 1996, Metabolism: clinical and experimental.

[57]  Siavash Ghaffari,et al.  A candidate prostate cancer susceptibility gene at chromosome 17p , 2001, Nature Genetics.

[58]  A. Hartmann,et al.  SAF-B protein couples transcription and pre-mRNA splicing to SAR/MAR elements. , 1998, Nucleic acids research.

[59]  B. Graveley.  Sorting out the complexity of SR protein functions. , 2000, RNA.

[60]  Arnold Munnich,et al.  Correlation between severity and SMN protein level in spinal muscular atrophy , 1997, Nature Genetics.

[61]  Gerald M. Rubin,et al.  The draft sequences: Comparing species , 2001, Nature.

[62]  Jiuyong Xie,et al.  Control of alternative splicing of potassium channels by stress hormones. , 1998, Science.

[63]  Lin Jin,et al.  Aberrant RNA Processing in a Neurodegenerative Disease: the Cause for Absent EAAT2, a Glutamate Transporter, in Amyotrophic Lateral Sclerosis , 1998, Neuron.

[64]  L. Bracco,et al.  The relevance of alternative RNA splicing to pharmacogenomics. , 2003, Trends in biotechnology.

[65]  C. Mann,et al.  Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[66]  R. Frants,et al.  An acceptor splice site mutation in intron 16 of the low density lipoprotein receptor gene leads to an elongated, internalization defective receptor. , 1993, Atherosclerosis.

[67]  Y. Eto,et al.  Single exon mutation in arylsulfatase A gene has two effects: loss of enzyme activity and aberrant splicing , 1994, Human Genetics.

[68]  A. Weiss,et al.  A CD45 Polymorphism Associated with Multiple Sclerosis Disrupts an Exonic Splicing Silencer* , 2001, The Journal of Biological Chemistry.

[69]  J. Reiss,et al.  Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B. , 1999, American journal of human genetics.

[70]  D. Hunt,et al.  A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). , 2001, Molecular cell.

[71]  T. Cooper,et al.  RNA processing and human disease , 2000, Cellular and Molecular Life Sciences CMLS.

[72]  D. Mackey,et al.  Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13). , 2001, Human molecular genetics.

[73]  Matthias W. Hentze,et al.  Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia , 2001, Nature Genetics.

[74]  T. Dörk,et al.  A new type of mutation causes a splicing defect in ATM , 2002, Nature Genetics.

[75]  M. Shapira,et al.  A transcription-activating polymorphism in the ACHE promoter associated with acute sensitivity to anti-acetylcholinesterases. , 2000, Human molecular genetics.

[76]  M. Meaney,et al.  5'-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: differential regulation of variant transcripts by early-life events. , 2000, Molecular endocrinology.

[77]  A Bairoch,et al.  The human proteomics initiative (HPI). , 2001, Trends in biotechnology.

[78]  B. McEwen.  Stress and hippocampal plasticity. , 1999, Annual review of neuroscience.

[79]  A. Kornblihtt,et al.  Coupling of transcription with alternative splicing: RNA pol II promoters modulate SF2/ASF and 9G8 effects on an exonic splicing enhancer. , 1999, Molecular cell.

[80]  B. Sullenger,et al.  Ribozyme-Mediated Repair of Sickle β-Globin mRNAs in Erythrocyte Precursors , 1998 .

[81]  J. Manley,et al.  SR proteins and splicing control. , 1996, Genes & development.

[82]  T. Cooper,et al.  Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. , 1998, Science.

[83]  Michael Ruogu Zhang,et al.  An alternative-exon database and its statistical analysis. , 2000, DNA and cell biology.

[84]  L. Nabors,et al.  HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine- and uridine-rich elements within the 3' untranslated regions of cytokine and angiogenic factor mRNAs. , 2001, Cancer research.

[85]  E. Aronica,et al.  Increased Expression of Neuronal Nitric Oxide Synthase Spliced Variants in Reactive Astrocytes of Amyotrophic Lateral Sclerosis Human Spinal Cord , 2001, The Journal of Neuroscience.

[86]  Alexander Rich,et al.  RNA processing and the evolution of eukaryotes , 1999, Nature Genetics.

[87]  Timothy R. Rebbeck,et al.  Assessing the function of genetic variants in candidate gene association studies , 2004, Nature Reviews Genetics.

[88]  B. Kerem,et al.  The molecular basis of partial penetrance of splicing mutations in cystic fibrosis. , 1997, American journal of human genetics.

[89]  W. Keller,et al.  RNA editing by base deamination: more enzymes, more targets, new mysteries. , 2001, Trends in biochemical sciences.

[90]  A. Krainer,et al.  Pre-mRNA splicing in the new millennium. , 2001, Current opinion in cell biology.

[91]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[92]  J. Genest,et al.  Familial hypercholesterolemia. Acceptor splice site (G-->C) mutation in intron 7 of the LDL-R gene: alternate RNA editing causes exon 8 skipping or a premature stop codon in exon 8. LDL-R(Honduras-1) [LDL-R1061(-1) G-->C]. , 1999, Atherosclerosis.

[93]  S. Stamm,et al.  Characterization and comparison of four serine- and arginine-rich (SR) protein kinases. , 1997, The Biochemical journal.

[94]  R Kole,et al.  Restoration of hemoglobin A synthesis in erythroid cells from peripheral blood of thalassemic patients. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[95]  M. Hentze,et al.  A Perfect Message RNA Surveillance and Nonsense-Mediated Decay , 1999, Cell.

[96]  G. Dreyfuss,et al.  Nuclear mRNA binding proteins couple pre-mRNA splicing and post-splicing events. , 2001, Molecules and cells.

[97]  P. Peterlongo,et al.  RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia. , 2000, Human molecular genetics.

[98]  David Valle,et al.  The skipping of constitutive exons in vivo induced by nonsense mutations , 1993, Science.

[99]  R. Reenan,et al.  A-to-I Pre-mRNA Editing in Drosophila Is Primarily Involved in Adult Nervous System Function and Integrity , 2000, Cell.

[100]  L. Staudt,et al.  Circulating human B cells that express surrogate light chains and edited receptors , 2000, Nature Immunology.

[101]  A. Kornblihtt,et al.  Alternative splicing: multiple control mechanisms and involvement in human disease. , 2002, Trends in genetics : TIG.

[102]  Peter Stoilov,et al.  Misregulation of pre-mRNA splicing that causes human diseases , 2000 .

[103]  P. Reitsma,et al.  A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. , 1996, Blood.

[104]  X. Estivill,et al.  Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1. , 2000, Human molecular genetics.

[105]  A. Hartmann,et al.  The STAR/GSG Family Protein rSLM-2 Regulates the Selection of Alternative Splice Sites* , 2001, The Journal of Biological Chemistry.

[106]  B. Sullenger,et al.  Ribozyme-mediated repair of sickle beta-globin mRNAs in erythrocyte precursors. , 1998, Science.

[107]  B R Franza,et al.  Regulated tissue-specific expression of antagonistic pre-mRNA splicing factors. , 1998, RNA.

[108]  P. Marynen,et al.  NXF5, a novel member of the nuclear RNA export factor family, is lost in a male patient with a syndromic form of mental retardation , 2001, Current Biology.

[109]  S. Stamm,et al.  Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[110]  T. Tabira,et al.  FTDP‐17 mutations N279K and S305N in tau produce increased splicing of exon 10 , 1999, FEBS letters.

[111]  B. Bass,et al.  Inosine exists in mRNA at tissue‐specific levels and is most abundant in brain mRNA , 1998, The EMBO journal.

[112]  N. Navaratnam,et al.  RNA editing: cytidine to uridine conversion in apolipoprotein B mRNA. , 2000, Biochimica et biophysica acta.

[113]  T. Crawford,et al.  The survival motor neuron protein in spinal muscular atrophy. , 1997, Human molecular genetics.

[114]  T. Maniatis,et al.  The function of multisite splicing enhancers. , 1998, Molecular cell.

[115]  W. Hauswirth,et al.  Ribozyme gene therapy: applications for molecular medicine. , 2001, Trends in molecular medicine.

[116]  D. Kaufer,et al.  Antisense prevention of neuronal damages following head injury in mice , 2000, Journal of Molecular Medicine.

[117]  A. Fire,et al.  Specific interference by ingested dsRNA , 1998, Nature.

[118]  Phillip D. Zamore,et al.  RNA interference: listening to the sound of silence , 2001, Nature Structural Biology.

[119]  D. Rujescu,et al.  Regulation of Alternative Splicing of Human Tau Exon 10 by Phosphorylation of Splicing Factors , 2001, Molecular and Cellular Neuroscience.

[120]  Christopher J. Lee,et al.  Genome-wide detection of alternative splicing in expressed sequences of human genes , 2001, Nucleic Acids Res..

[121]  D. Kaufer,et al.  Acute stress facilitates long-lasting changes in cholinergic gene expression , 1998, Nature.

[122]  S. Stamm,et al.  Emerin interacts in vitro with the splicing-associated factor, YT521-B. , 2003, European journal of biochemistry.

[123]  T. Maniatis,et al.  An extensive network of coupling among gene expression machines , 2002, Nature.

[124]  D. Thiele,et al.  The Mammalian HSF4 Gene Generates Both an Activator and a Repressor of Heat Shock Genes by Alternative Splicing* , 1999, The Journal of Biological Chemistry.

[125]  Molly M. Huntsman,et al.  Altered ratios of alternatively spliced long and short γ2 subunit mRNAs of the γ-amino butyrate type A receptor in prefrontal cortex of schizophrenics , 1998 .

[126]  B. Schrank,et al.  Reduced survival motor neuron (Smn) gene dose in mice leads to motor neuron degeneration: an animal model for spinal muscular atrophy type III. , 2000, Human molecular genetics.

[127]  G. Isshiki,et al.  Two mutations remote from an exon/intron junction in the β-hexosaminidase β-subunit gene affect 3’-splice site selection and cause Sandhoff disease , 1998, Human Genetics.

[128]  Juri Rappsilber,et al.  Mass spectrometry and EST-database searching allows characterization of the multi-protein spliceosome complex , 1998, Nature Genetics.

[129]  T. Cooper,et al.  The regulation of splice-site selection, and its role in human disease. , 1997, American journal of human genetics.

[130]  Bernhard Hemmer,et al.  A point mutation in PTPRC is associated with the development of multiple sclerosis , 2000, Nature Genetics.

[131]  T. Cooper,et al.  Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy , 2001, Nature Genetics.

[132]  M. Gelfand,et al.  Evolution of the Exon–Intron Structure and Alternative Splicing of the MAGE-A Family of Cancer/Testis Antigens , 2004, Journal of Molecular Evolution.

[133]  Brenda L Bass,et al.  RNA editing by adenosine deaminases that act on RNA. , 2002, Annual review of biochemistry.

[134]  T. Tuschl,et al.  Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells , 2001, Nature.

[135]  C. Lorson,et al.  A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[136]  Y. Zhang,et al.  A splicing variant of a death domain protein that is regulated by a mitogen-activated kinase is a substrate for c-Jun N-terminal kinase in the human central nervous system. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[137]  R Kole,et al.  Modification of alternative splicing pathways as a potential approach to chemotherapy. , 2000, Pharmacology & therapeutics.

[138]  A. Krainer,et al.  Listening to silence and understanding nonsense: exonic mutations that affect splicing , 2002, Nature Reviews Genetics.

[139]  M. Goodson,et al.  Tissue-dependent expression of heat shock factor 2 isoforms with distinct transcriptional activities , 1995, Molecular and cellular biology.

[140]  A. Krainer,et al.  The Mkk3/6-p38–Signaling Cascade Alters the Subcellular Distribution of Hnrnp A1 and Modulates Alternative Splicing Regulation , 2000, The Journal of cell biology.

[141]  X. Estivill,et al.  Cold shock induces the insertion of a cryptic exon in the neurofibromatosis type 1 (NF1) mRNA. , 2000, Nucleic acids research.

[142]  R. Reenan.  The RNA world meets behavior: A-->I pre-mRNA editing in animals. , 2001, Trends in genetics : TIG.

[143]  M. Goedert,et al.  Tau gene mutations and tau pathology in frontotemporal dementia and parkinsonism linked to chromosome 17. , 2001, Advances in experimental medicine and biology.

[144]  D. Rodriguez,et al.  Aberrant Splicing of Exon 6 in the Pyruvate Denydrogenase-Elα mRNA Linked to a Silent Mutation in a Large Family with Leigh's Encephalomyelopathy , 1994, Pediatric Research.

[145]  L. Maquat,et al.  Quality Control of mRNA Function , 2001, Cell.

[146]  Kavita Shah,et al.  ERK phosphorylation drives cytoplasmic accumulation of hnRNP-K and inhibition of mRNA translation , 2001, Nature Cell Biology.

[147]  K. Nakai,et al.  Construction of a novel database containing aberrant splicing mutations of mammalian genes. , 1994, Gene.

[148]  S. Catts,et al.  Increased levels of expression of an NMDAR1 splice variant in the superior temporal gyrus in schizophrenia , 2000, Neuroreport.

[149]  P. Schofield,et al.  Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene , 2000 .

[150]  Y. Seyama,et al.  Silent nucleotide substitution in the sterol 27-hydroxylase gene (CYP 27) leads to alternative pre-mRNA splicing by activating a cryptic 5' splice site at the mutant codon in cerebrotendinous xanthomatosis patients. , 1998, Biochemistry.

[151]  D. Weatherall,et al.  Clinical features and molecular analysis of acquired hemoglobin H disease. , 1983, The American journal of medicine.

[152]  B. Graveley.  Alternative splicing: increasing diversity in the proteomic world. , 2001, Trends in genetics : TIG.

[153]  D. Kaufer,et al.  Alternative Splicing and Neuritic mRNA Translocation Under Long-Term Neuronal Hypersensitivity , 2002, Science.

[154]  Douglas S. Portman,et al.  Cell type-specific expression of hnRNP proteins. , 1995, Experimental cell research.

[155]  T. Misteli,et al.  Correction of Alternative Splicing of Tau in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17* , 2001, The Journal of Biological Chemistry.

[156]  B. Kerem,et al.  The Molecular Basis for Disease Variability in Cystic Fibrosis , 1996, European journal of human genetics : EJHG.

[157]  Y. Shiloh,et al.  Predominance of null mutations in ataxia-telangiectasia. , 1996, Human molecular genetics.

[158]  T A Thanaraj,et al.  Human GC-AG alternative intron isoforms with weak donor sites show enhanced consensus at acceptor exon positions. , 2001, Nucleic acids research.

[159]  M. Suyama,et al.  TAP (NXF1) Belongs to a Multigene Family of Putative RNA Export Factors with a Conserved Modular Architecture , 2000, Molecular and Cellular Biology.

[160]  A Klug,et al.  Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[161]  E J Steinmetz,et al.  Pre-mRNA Processing and the CTD of RNA Polymerase II: The Tail That Wags the Dog? , 1997, Cell.

[162]  R. Rabinovici,et al.  ADAR1 Is Involved in the Development of Microvascular Lung Injury , 2001, Circulation research.

[163]  A. Kornblihtt,et al.  Coordination between transcription and pre‐mRNA processing , 2001, FEBS letters.

[164]  I. Kanazawa,et al.  Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis , 1999, Annals of neurology.

[165]  Y. Jong,et al.  Treatment of spinal muscular atrophy by sodium butyrate , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[166]  U. Monani,et al.  The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy. , 2000, Human molecular genetics.

[167]  D. Cooper,et al.  The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: Causes and consequences , 1992, Human Genetics.

[168]  W. Silvers,et al.  Selective increase in specific alternative splice variants of tyrosinase in murine melanomas: a projected basis for immunotherapy. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[169]  P. Beverley,et al.  A point mutation within CD45 exon A is the cause of variant CD45RA splicing in humans , 1998, European journal of immunology.

[170]  C. Lorson,et al.  An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. , 2000, Human molecular genetics.

[171]  P. Babitzke,et al.  Myotonic dystrophy: molecular windows on a complex etiology. , 1998, Nucleic acids research.

[172]  B. Poll-The,et al.  Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship , 2004, Human Genetics.

[173]  E. Androphy,et al.  Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. , 2001, Human molecular genetics.

[174]  R. Pergolizzi,et al.  Abnormal splice in a mutant human beta-globin gene not at the site of a mutation. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[175]  D. Kaufer,et al.  Frequent Blood–Brain Barrier Disruption in the Human Cerebral Cortex , 2001, Cellular and Molecular Neurobiology.

[176]  B. Brais,et al.  Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy , 1998, Nature Genetics.

[177]  M. Hübener,et al.  Activity‐dependent regulation of alternative splicing patterns in the rat brain , 1999, The European journal of neuroscience.

[178]  M. Garcia-Blanco,et al.  Repair of CFTR mRNA by spliceosome-mediated RNA trans-splicing , 2000, Gene Therapy.

[179]  Stefan Stamm,et al.  Signals and their transduction pathways regulating alternative splicing: a new dimension of the human genome. , 2002, Human molecular genetics.

[180]  Osamu Hori,et al.  A Novel Presenilin‐2 Splice Variant in Human Alzheimer's Disease Brain Tissue , 1999, Journal of neurochemistry.

[181]  S. Akbarian,et al.  Editing for an AMPA receptor subunit RNA in prefrontal cortex and striatum in Alzheimer's disease, Huntington's disease and schizophrenia , 1995, Brain Research.

[182]  J. Weissenbach,et al.  Identification and characterization of a spinal muscular atrophy-determining gene , 1995, Cell.

[183]  B. Kerem,et al.  Splicing regulation as a potential genetic modifier. , 2002, Trends in genetics : TIG.

[184]  P. Nürnberg,et al.  Nearby stop codons in exons of the neurofibromatosis type 1 gene are disparate splice effectors. , 1998, American journal of human genetics.

[185]  R. Emeson,et al.  Functions and mechanisms of RNA editing. , 2000, Annual review of genetics.

[186]  S. Noselli,et al.  MKK7 Is A Stress-activated Mitogen-activated Protein Kinase Kinase Functionally Related to hemipterous * , 1997, The Journal of Biological Chemistry.

[187]  Alexandros D. Polydorides,et al.  The splice of life: Alternative splicing and neurological disease , 2001, Nature Reviews Neuroscience.

[188]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[189]  J. A. Steitz,et al.  HuR and mRNA stability , 2001, Cellular and Molecular Life Sciences CMLS.