Nonsense-mediated mRNA decay (NMD) is a widespread quality control mechanism in eukaryotic cells. It can recognize and degrade aberrant transcripts harbouring a premature translational termination codon (PTC), and thereby prevent the production of C-terminally truncated proteins which might be deleterious. Approximately, 30% of human genetic diseases are caused by transcripts containing PTCs. These transcripts are potential targets of NMD. As for monogenic diseases, NMD has effects on the phenotype or mode of inheritance. Here, we explain the mechanism of this surveillance pathway, and take several neuromuscular disorders as examples to discuss its influence for human monogenic diseases. The deeper understanding for NMD will shed light on the nosogenesis and therapies of monogenic diseases.
GUO Wen-Ting, XU Wang-Yang, GU Ming-Min
. Nonsense-mediated mRNA decay and human monogenic disease[J]. Hereditas(Beijing), 2012
, 34(8)
: 935
-942
.
DOI: 10.3724/SP.J.1005.2012.00935
[1] Nicholson P, Yepiskoposyan H, Metze S, Zamudio Orozco R, Kleinschmidt N, Mühlemann O. Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors. Cell Mol Life Sci, 2010, 67(5): 677-700.
[2] Losson R, Lacroute F. Interference of nonsense mutations with eukaryotic messenger RNA stability. Proc Natl Acad Sci USA, 1979, 76(10): 5134-5137.
[3] Maquat LE, Kinniburgh AJ, Rachimilewiz EA, Ross J. Unstable beta-globin mRNA in mRNA-deficient beta (0) thalassemia. Cell, 1981, 27(3 Pt 2): 543-553.
[4] Bhuvanagiri M, Schlitter AM, Hentze MW, Kulozik AE. NMD: RNA biology meets human genetic medicine. Biochem J, 2010, 430(3): 365-377.
[5] Culbertson MR. RNA surveillance. Unforeseen conse-quences for gene expression, inherited genetic disorders and cancer. Trends Genet, 1999, 15(2): 74-80.
[6] Franks TM, Singh G, Lykke-Andersen J. Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense-mediated mRNA decay. Cell, 2010, 143(6): 938-950.
[7] Durand S, Lykke-Andersen J. SnapShot: nonsense-mediated mRNA decay. Cell, 2011, 145(2): 324.
[8] Chang YF, Imam JS, Wilkinson MF. The nonsense-mediated decay RNA surveillance pathway. Annu Rev Bio-chem, 2007, 76(1): 51-74.
[9] Hwang J, Maquat LE. Nonsense-mediated mRNA decay (NMD) in animal embryogenesis: to die or not to die, that is the question. Curr Opin Genet Dev, 2011, 21(4): 422-430.
[10] Maquat LE, Tarn WY, Isken O. The pioneer round of translation: features and functions. Cell, 2010, 142(3): 368-374.
[11] Kadlec J, Izaurralde E, Cusack S. The structural basis for the interaction between nonsense-mediated mRNA decay factors UPF2 and UPF3. Nat Struct Mol Biol, 2004, 11(4): 330-337.
[12] Gehring NH, Lamprinaki S, Hentze MW, Kulozik AE, Misteli T. The hierarchy of exon-junction complex assembly by the spliceosome explains key features of mammalian nonsense-mediated mRNA decay. PLoS Biol, 2009, 7(5): e1000120.
[13] Wang J, Gudikote JP, Olivas OR, Wilkinson MF. Bound-ary-independent polar nonsense-mediated decay. EMBO Rep, 2002, 3(3): 274-279.
[14] Cusack BP, Arndt PF, Duret L, Roest Crollius H, Zhang J Z. Preventing dangerous nonsense: selection for robust-ness to transcriptional error in human genes. PLoS Genet, 2011, 7(10): e1002276.
[15] Rebbapragada I, Lykke-Andersen J. Execution of non-sense-mediated mRNA decay: what defines a substrate? Curr Opin Cell Biol, 2009, 21(3): 394-402.
[16] Hogg JR, Goff SP. Upf1 senses 3’UTR length to potentiate mRNA decay. Cell, 2010, 143(3): 379-389.
[17] Bühler M, Steiner S, Mohn F, Paillusson A, Mühlemann O. EJC-independent degradation of nonsense immunoglobu-lin-mu mRNA depends on 3' UTR length. Nat Struct Mol Biol, 2006, 13(5): 462-464.
[18] Wen J, Brogna S. Splicing-dependent NMD does not require the EJC in Schizosaccharomyces pombe. EMBO J, 2010, 29(9): 1537-1551.
[19] Forget BG, Benz EJ Jr, Skoultchi A, Baglioni C, Housman D. Absence of messenger RNA for beta globin chain in β0 thalassaemia. Nature, 1974, 247(440): 379-381.
[20] Baserga SJ, Benz EJ Jr. Nonsense mutations in the human beta-globin gene affect mRNA metabolism. Pro Natl Acad Sci USA, 1988, 85(7): 2056-2060.
[21] Hall GW, Thein S. Nonesense codon mutations in the terminal exon of the β-mRNA accumulation: a mechanism for the phenotype of dominant β-thalassemia. Blood, 1994, 83(8): 2031-2037.
[22] Gerards M, van den Bosch B, Calis C, Schoonderwoerd K, van Engelen K, Tijssen M, de Coo R, van der Kooi A, Smeets H. Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy. Mito-chondrion, 2010, 10(5): 510-515.
[23] Isidor B, Lindenbaum P, Pichon
