RNA Processing and Human Disorders


Errors in messenger ribonucleic acid biogenesis at any one of a number of steps often result in human disease because of the failure to synthesize functional protein.

Keywords: Splicing; 3′end formation; editing; defective RNA processing; human diseases

Figure 1.

Overview of the steps involved in human gene expression. In the nucleus, genes are transcribed to form pre‐mRNA. Pre‐mRNA, which is characterized by a 7‐methylGpppG cap structure that is added cotranscriptionally, is then processed to mRNA. Processing includes (i) splicing, that is the ligation of exons (boxes) and the concomitant removal of intervening sequences or introns (lines between boxes), and (ii) 3′ end formation, that is endonucleolytic cleavage followed by the addition of poly(A) ((A)n) to the upstream cleavage product. Depending on the particular transcript and type of editing, editing can occur either before or after splicing. Finally, processed mRNA is exported to the cytoplasm, where it is translated and, ultimately, degraded. The translation initiation codon usually resides within the first exon, and the translation termination codon usually resides within the last exon.

Figure 2.

Examples of splicing defects that alter the coding sequence of a gene. AUG and Norm Stop specify the initiation codon and the normal termination codon, respectively, while STOP signs specify premature termination codons. Patterned boxes and thick lines represent exons and introns respectively. Thin and dashed lines connect normally used and abnormally used (cryptic) 5′ and 3′ splice sites (ss) respectively. Intron retention can result in an intron‐derived premature termination codon, a shift in the reading frame that generates a downstream premature termination codon or an insertion in the reading frame. Exon skipping can result in a shift in the reading frame that generates a downstream premature termination codon or deletion of the reading frame.

Figure 3.

Intronic mutation can create a new splice site within β‐globin pre‐mRNA. Splicing of exon 1 (E1), exon 2 (E2) and exon 3 (E3) of a normal (a) or mutated (b) β‐globin pre‐mRNA that harbours a U‐to‐G transversion (bold capital letters) within the second of two introns (thick bold lines). In the case of the mutated pre‐mRNA, the transversion is recognized as a 5′ splice site and is paired with a cryptic 3′ splice site that resides upstream. As a consequence, an intronic region (dotted box) that harbours a premature termination codon is retained in the spliced product so that it encodes abnormal β‐globin protein.

Figure 4.

Deletion within the polyadenylation sequence of the α2‐globin gene can lead to decreased expression of both α2‐ and α1‐globin genes. 3′ end formation of a normal (a) or mutated α2‐globin gene (b) that lacks the last two base pairs of the polyadenylation sequence (bold ΔΔ). In the case of the mutated gene, 3′ end formation is inefficient, causing transcription termination to be inefficient. As a consequence, transcription of the downstream α1‐globin gene is compromised, and the α2‐globin transcript is unstable.



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Further Reading

Cartegni L, Chew SL and Krainer AR (2002) Listening to silence and understanding nonsense; exonic mutations that affect splicing. Nature Reviews Genetics 3: 285–298.

Cooper TA and Mattox W (1997) The regulation of splice‐site selection, and its role in human disease. American Journal of Human Genetics 61: 259–266.

Keegan LP, Gallo A and O’Connell MA (2001) The many roles of an RNA editor. Nature Reviews 2: 869–878.

Maquat LE and Carmichael GG (2001) Quality control of mRNA function. Cell 104: 173–176.

Web Links

Breast cancer 1, early onset (BRCA1); LocusID: 672. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=672.

Neurofibromin 1 (NF1); LocusID: 4763. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=4763.

Protein tyrosine phosphatase, receptor type, C (PTPRC); LocusID: 5788. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5788.

Breast cancer 1, early onset (BRCA1); MIM number: 113705. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/ dispmim?113705.

Neurofibromin 1 (NF1); MIM number: 162200. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/ dispmim?162200.

Protein tyrosine phosphatase, receptor type, C (PTPRC); MIM number: 151460. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?151460.

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How to Cite close
Lejeune, Fabrice, and Maquat, Lynne E(Jan 2007) RNA Processing and Human Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005495.pub2]