関: nonsense mutation、premature stop codon、premature termination codon

WordNet

having no intelligible meaning; "nonsense syllables"; "a nonsensical jumble of words" (同)nonsensical
a message that seems to convey no meaning (同)bunk, nonsensicality, meaninglessness, hokum
major food fish of Arctic and cold-temperate waters (同)codfish
lean white flesh of important North Atlantic food fish; usually baked or poached (同)codfish
a specific sequence of three adjacent nucleotides on a strand of DNA or RNA that specifies the genetic code information for synthesizing a particular amino acid

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『無意味な言葉』(『行為』),たわごと;ばかげた考え(振舞い) / くだらないこと(もの)(trifles) / ばかな,くだらん
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/09 12:42:50」(JST)

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In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation where a single nucleotide is changed to cause substitution of a different amino acid. Some genetic disorders, such as thalassemia and DMD, result from nonsense mutations.

Simple example

    DNA: 5' - ATG ACT CAC CGA GCG CGA AGC TGA - 3'
         3' - TAC TGA GTG GCT CGC GCT TCG ACT - 5'
   mRNA: 5' - AUG ACU CAC CGA GCG CGA AGC UGA - 3'
Protein:      Met Thr His Arg Ala Arg Ser Stop

Suppose that a nonsense mutation was introduced at the fourth triplet in the DNA sequence (CGA) causing the cytosine to be replaced with thymine, yielding TGA in the DNA sequence. Since TGA is transcribed-then-translated as UGA, the resulting transcript and protein product would be:

    DNA: 5' - ATG ACT CAC TGA GCG CGA AGC TGA - 3'
         3' - TAC TGA GTG ACT CGC GCT TCG ACT - 5'
   mRNA: 5' - AUG ACU CAC UGA GCG CGU AGC UGA - 3'
Protein:      Met Thr His Stop

The remaining codons of the mRNA are not translated into amino proteins because the stop codon is prematurely reached during translation. This can yield a truncated abbreviated protein product, which quite often lacks the functionality of the normal, non-mutant protein.

Nonsense-mediated mRNA decay

Despite an expected tendency for premature termination codons to yield shortened polypeptide products, in fact the formation of truncated proteins does not occur often in vivo. Many organisms—including humans and lower species, such as yeast—employ a nonsense-mediated mRNA decay pathway, which degrades mRNAs containing nonsense mutations before they are translated into nonfunctional polypeptides.

The three stop codons have been given names: UAG is amber, UGA is opal (sometimes also called umber), and UAA is ochre. “Amber” was named by discoverers Richard Epstein and Charles Steinberg after their friend Harris Bernstein, whose last name means “amber” in German.^[1] The other two stop codons were named “ochre” and “opal” in order to keep the “color names” theme. Stop codons are also called “termination”or “nonsense” codons. They signal release of the nascent polypeptide from the ribosome because there is no cognate tRNA that has anticodons complementary to these stop signals, and so a release factor binds to the ribosome instead.

Pathology associated with nonsense mutations

Selection of notable mutations, ordered in a standard table of the genetic code of amino acids.^[2] Nonsense mutations are marked by red arrows.

Nonsense mutations can cause a genetic disease by damaging a gene responsible for a specific protein, for example, dystrophin in Duchenne muscular dystrophy. The same disease may, however, be caused by other kinds of damage to the same gene. Examples of diseases in which nonsense mutations are known to be among the causes include:

Cystic fibrosis (caused by the G542X mutation in the cystic fibrosis transmembrane conductance regulator gene).

Duchenne muscular dystrophy (dystrophin)

Beta thalassaemia (β-globin)

Hurler syndrome

An experimental drug known as PTC124 may be useful in treating some cases of each of the above diseases (that is, the cases caused by a nonsense mutation). PTC124 was scheduled to enter the final phase of clinical trials in 2007.

^[3]

External links and references

^ Edgar B (October 2004). "The genome of bacteriophage T4: an archeological dig". Genetics 168 (2): 575–82. PMC 1448817. PMID 15514035.
^ References for the image are found in Wikimedia Commons page at: Commons:File:Notable mutations.svg#References.
^ Henderson, Mark (23 April 2007). "Daily pill to beat genetic diseases". The Times (London). Retrieved 2007-10-23.

Mutations
Nonsense mutation (Medical dictionary)
Gatfield D, Unterholzner L, Ciccarelli FD, Bork P, Izaurralde E (1 August 2003). "Nonsense-mediated mRNA decay in Drosophila: at the intersection of the yeast and mammalian pathways". The EMBO Journal 22 (15): 3960–70. doi:10.1093/emboj/cdg371. PMC 169044. PMID 12881430.
Welch EM, et al. (3 May 2007). "PTC124 targets genetic disorders caused by nonsense mutations". Nature 447 (7140): 87–91. doi:10.1038/nature05756. PMID 17450125.

UpToDate Contents

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English Journal

Testing the faux-UTR model for NMD: Analysis of Upf1p and Pab1p competition for binding to eRF3/Sup35p.

Kervestin S, Li C, Buckingham R, Jacobson A.SourceCNRS UPR9073 Associated with Université Paris Diderot, Sorbonne Paris Cité, Institut de Biologie Physico-chimique (IBPC) 13 rue Pierre et Marie Curie, 75005 Paris, France.
Biochimie.Biochimie.2012 Jul;94(7):1560-71. Epub 2012 Jan 2.
Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that accelerates the degradation of mRNAs containing premature translation termination codons. This quality control pathway depends on the NMD-specific factors, Upf1p, Upf2p/Nmd2p, and Upf3p, as well as the two release factors, eRF1 and
PMID 22227378

Nonsense mediated decay of VWF mRNA subsequent to c.7674-7675insC mutation in type3 VWD patients.

Shahbazi S, Baniahmad F, Zakiani-Roudsari M, Raigani M, Mahdian R.SourceDepartment of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Blood cells, molecules & diseases.Blood Cells Mol Dis.2012 Jun 15;49(1):48-52. Epub 2012 Apr 12.
Von Willebrand disease (VWD), the most common genetic bleeding disorder, is caused by defects in Von Willebrand factor (VWF). Quantitative deficiencies of the protein lead to either VWD type3, the severe form of the disease or VWD type1 with milder clinical manifestation. Null alleles are the most c
PMID 22503077

Japanese Journal

Nonsense-mediated mRNA decay was demonstrated in two hypofibrinogenemias caused by heterozygous nonsense mutations of FGG, Shizuoka III and Kanazawa II

Soya Keisuke,Takezawa Yuka,Okumura Nobuo,Terasawa Fumiko
THROMBOSIS RESEARCH 132(4), 465-470, 2013-10
… To demonstrate the involvement of the mechanisms of nonsense-mediated mRNA decay (NMD), we cloned wild- and mutant-type mini-genes containing γ23 or γ376 codon and transfected these into CHO cell lines in the absence or presence of cycloheximide as an NMD inhibitor. …
NAID 120005366103

人間ドック時の特徴的な食道病変を契機に診断されPTEN遺伝子(exon5)変異を認めた Cowden 病の1例

澤村紀子,原田直彦,伊原栄吉,柿ケ尾佳奈,杉満紀子,原口和大,水谷孝弘,吉本剛志,河邉顕,福嶋伸良,福泉公仁隆,中牟田誠,吉村理江,中村和彦
日本消化器病學會雜誌 = The Japanese journal of gastro-enterology 109(4), 593-599, 2012-04-05
… 症例は50歳代男性．病歴は，2009年Cowden病を疑われ当科紹介受診．歯肉の結節状乳頭腫，手掌に角化性丘疹，食道に多発小隆起，直腸神経鞘腫，腺腫様甲状腺腫を認め，Cowden病の診断に至った．PTEN遺伝子exon5 codon130に変異（CGA→TGA）を認めた．Cowden病は悪性腫瘍を合併する頻度が高いため，慎重な経過観察が必要である． …
NAID 10030560566

Genome Features of "Dark-Fly", a Drosophila Line Reared Long-Term in a Dark Environment

Izutsu Minako,Zhou Jun,Sugiyama Yuzo,Nishimura Osamu,Aizu Tomoyuki,Toyoda Atsushi,Fujiyama Asao,Agata Kiyokazu,Fuse Naoyuki
PLoS ONE 7(3), e33288, 2012-03-14
… Among them, we detected 28 nonsense mutations (i.e., they produce a stop codon in the protein sequence) in the Dark-fly genome. …
NAID 120003892186

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リンク元	「終止コドン」「premature stop codon」「premature termination codon」「ナンセンスコドン」
関連記事	「cod」「nonsense」