Splicing regulation as a potential genetic modifier.

Inherited diseases are associated with profound phenotypic variability, which is affected strongly by genetic modifiers. The splicing machinery could be one such modifying system, through a mechanism involving splicing motifs and their interaction with a complex repertoire of splicing factors. Mutations in splicing motifs and changes in levels of splicing factors can result in different splicing patterns. Changes in the level of normal transcripts or in the relative pattern of different mRNA isoforms affect disease expression, leading to phenotypic variability. Here, we discuss the splicing machinery in terms of its significance in disease severity and its potential role as a genetic modifier.

[1]  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.

[2]  L. Tsui,et al.  Higher proportion of intact exon 9 CFTR mRNA in nasal epithelium compared with vas deferens. , 1997, Human molecular genetics.

[3]  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.

[4]  C. Croce,et al.  Aberrant FHIT transcripts in Merkel cell carcinoma. , 1996, Cancer research.

[5]  D. Gotley,et al.  Expression of antisense CD44 variant 6 inhibits colorectal tumor metastasis and tumor growth in a wound environment. , 1998, Cancer research.

[6]  T. Gilliam,et al.  Differential SMN2 expression associated with SMA severity , 1998, Nature Genetics.

[7]  P. Lantos,et al.  A novel tau mutation (N296N) in familial dementia with swollen achromatic neurons and corticobasal inclusion bodies , 2000, Annals of neurology.

[8]  C Maayan,et al.  Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. , 2001, American journal of human genetics.

[9]  J. Figge,et al.  Restricted patterns of CD44 variant exon expression in human papillary thyroid carcinoma. , 1996, Cancer research.

[10]  Joseph H. Nadeau,et al.  Modifier genes in mice and humans , 2001, Nature Reviews Genetics.

[11]  Y. Takeshima,et al.  Disruption of the splicing enhancer sequence within exon 27 of the dystrophin gene by a nonsense mutation induces partial skipping of the exon and is responsible for Becker muscular dystrophy. , 1997, The Journal of clinical investigation.

[12]  J. Jääskeläinen,et al.  Mild familial neurofibromatosis 2 associates with expression of merlin with altered COOH-terminus , 2000, Neurology.

[13]  G M Lenoir,et al.  A BRCA1 nonsense mutation causes exon skipping. , 1998, American journal of human genetics.

[14]  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.

[15]  M. Herlyn,et al.  Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Tom Misteli,et al.  The dynamics of a pre-mRNA splicing factor in living cells , 1997, Nature.

[17]  Marc Fellous,et al.  Donor splice-site mutations in WT1 are responsible for Frasier syndrome , 1997, Nature Genetics.

[18]  J. Valcárcel,et al.  Nucleocytoplasmic Shuttling of Heterodimeric Splicing Factor U2AF* , 2001, The Journal of Biological Chemistry.

[19]  A. Zahler,et al.  Distinct functions of SR proteins in alternative pre-mRNA splicing. , 1993, Science.

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

[21]  S Rosenberg,et al.  Alternative and aberrant messenger RNA splicing of the mdm2 oncogene in invasive breast cancer. , 2001, Cancer research.

[22]  T. Barka.  Effect of sodium butyrate on the expression of genes transduced by retroviral vectors , 1998, Journal of cellular biochemistry.

[23]  C. Junien,et al.  WT1 splicing alterations in Wilms' tumors. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  J. G. Patton,et al.  Alternative splicing in the control of gene expression. , 1989, Annual review of genetics.

[25]  C. R. Valentine,et al.  The association of nonsense codons with exon skipping. , 1998, Mutation research.

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

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

[28]  J. Valcárcel,et al.  Alternative pre-mRNA splicing: the logic of combinatorial control. , 2000, Trends in biochemical sciences.

[29]  W. Lissens,et al.  Analysis of Exonic Mutations Leading to Exon Skipping in Patients with Pyruvate Dehydrogenase E1α Deficiency , 2000, Pediatric Research.

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

[31]  W. Lee,et al.  Soluble CD44 isoforms in serum as potential markers of metastatic gastric carcinoma. , 1996, Journal of clinical gastroenterology.

[32]  A. Krainer,et al.  Regulation of alternative splicing in vivo by overexpression of antagonistic splicing factors. , 1994, Science.

[33]  B. Kerem,et al.  Cellular and viral splicing factors can modify the splicing pattern of CFTR transcripts carrying splicing mutations. , 2000, Human molecular genetics.

[34]  J. T. Dunnen,et al.  Dystrophin nonsense mutation induces different levels of exon 29 skipping and leads to variable phenotypes within one BMD family , 2000, European Journal of Human Genetics.

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

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

[37]  B. Kerem,et al.  Variable levels of normal RNA in different fetal organs carrying a cystic fibrosis transmembrane conductance regulator splicing mutation. , 1999, American journal of respiratory and critical care medicine.

[38]  P Scambler,et al.  Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms. , 1998, Human molecular genetics.

[39]  P. Sharp,et al.  Splicing of messenger RNA precursors. , 1987, Science.

[40]  X. Estivill,et al.  Testicular CFTR splice variants in patients with congenital absence of the vas deferens. , 1998, Human molecular genetics.

[41]  P. Green,et al.  Analysis of expressed sequence tags indicates 35,000 human genes , 2000, Nature Genetics.

[42]  H. Miyake,et al.  Expression of CD44 adhesion molecules in nonpapillary renal cell carcinoma and normal kidneys. , 1999, Urology.

[43]  Y. Rao,et al.  Regulation of Ich-1 pre-mRNA alternative splicing and apoptosis by mammalian splicing factors. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

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

[45]  A. Krainer,et al.  The Subcellular Localization of SF2/ASF Is Regulated by Direct Interaction with SR Protein Kinases (SRPKs)* , 1999, The Journal of Biological Chemistry.

[46]  B. Kerem,et al.  The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C-->T mutation. , 1998, Genomics.

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

[48]  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.

[49]  C. Croce,et al.  FHIT gene alterations in head and neck squamous cell carcinomas. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[50]  I. Bièche,et al.  Increased level of exon 12 alternatively spliced BRCA2 transcripts in tumor breast tissue compared with normal tissue. , 1999, Cancer research.

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

[52]  A. Krainer,et al.  Pre-mRNA splicing in the absence of an SR protein RS domain. , 2000, Genes & development.

[53]  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.

[54]  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.

[55]  Z. Tümer,et al.  Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome. , 2000, American journal of human genetics.

[56]  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.