Widespread predicted nonsense-mediated mRNA decay of alternatively-spliced transcripts of human normal and disease genes

We have recently shown that a third of reliably-inferred alternative mRNA isoforms are candidates for nonsense-mediated mRNA decay (NMD), an mRNA surveillance system (Lewis et al., 2003; PROC: Natl Acad. Sci. USA, 100, 189-192). Rather than being translated to yield protein, these transcripts are expected to be degraded and may be subject to regulated unproductive splicing and translation (RUST). Our initial experimental studies are consistent with these predictions and suggest an unappreciated role for NMD in several human diseases.

[1]  D. Pollen,et al.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease , 1995, Nature.

[2]  Donna R. Maglott,et al.  RefSeq and LocusLink: NCBI gene-centered resources , 2001, Nucleic Acids Res..

[3]  J. Bell,et al.  LARD: a new lymphoid-specific death domain containing receptor regulated by alternative pre-mRNA splicing. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[4]  H. Le Hir,et al.  The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense‐mediated mRNA decay , 2001, The EMBO journal.

[5]  Maria Jesus Martin,et al.  High-quality Protein Knowledge Resource: SWISS-PROT and TrEMBL , 2002, Briefings Bioinform..

[6]  Tom H. Lindner,et al.  Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus , 2000, Nature Genetics.

[7]  L. Maquat,et al.  Evidence for a Pioneer Round of mRNA Translation mRNAs Subject to Nonsense-Mediated Decay in Mammalian Cells Are Bound by CBP80 and CBP20 , 2001, Cell.

[8]  S. Brenner,et al.  Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  M. W. Thompson,et al.  Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene. , 1989, American journal of human genetics.

[10]  W. Gish,et al.  Gene structure prediction and alternative splicing analysis using genomically aligned ESTs. , 2001, Genome research.

[11]  M Bobrow,et al.  Searching for the 1 in 2,400,000: A review of dystrophin gene point mutations , 1994, Human mutation.

[12]  David States,et al.  Selecting for functional alternative splices in ESTs. , 2002, Genome research.

[13]  A Sureau,et al.  SC35 autoregulates its expression by promoting splicing events that destabilize its mRNAs , 2001, The EMBO journal.

[14]  L. Maquat,et al.  A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. , 1998, Trends in biochemical sciences.

[15]  Naruhiko Sahara,et al.  Identification and characterization of presenilin I-467, I-463 and I-374 , 1996 .

[16]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[17]  J. Steitz,et al.  Human Upf Proteins Target an mRNA for Nonsense-Mediated Decay When Bound Downstream of a Termination Codon , 2000, Cell.

[18]  P Bork,et al.  EST comparison indicates 38% of human mRNAs contain possible alternative splice forms , 2000, FEBS letters.

[19]  M. Boguski,et al.  dbEST — database for “expressed sequence tags” , 1993, Nature Genetics.

[20]  Q. Mitrovich,et al.  Unproductively spliced ribosomal protein mRNAs are natural targets of mRNA surveillance in C. elegans. , 2000, Genes & development.