Chain termination mutation

MAOA activity have been implicated in a wide range of psychiatric disorders. Deficiency in MAOA enzyme activity due to a hemizygous chain termination mutation of the MAOA gene has recently been shown to be associated with impulsive aggression and hypersexual behavior in affected males from a single extended pedigree (Brunner syndrome) (Brunner et al. 1993). 

As discussed in the preceding section, the best known suppressor genes are those that suppress chain termination mutations (Section 6). These genes often encode mutant forms of tRNA molecules, which allow incorporation of an amino acid rather than chain... 

P53 is the most frequently mutated gene in human cancer, with an up to 50% mutation frequency in solid tumors. Most commonly, these genetic changes are missense mutations in one allele, although deletions or chain termination mutations can occur. 

C), the mutation is cdX cd temperature-sensitive (Ts) mutation. Sometimes no amino acid corresponds to a new base sequence (Chapter 25) in that case, termination of synthesis of the protein occurs at that point, and the mutation is called a chain termination mutation or nonsense mutation. These mutations generate one of the three nonsense codons UAA, UAG, or UGA (Chapter 25). 

The answer is e. (Murray, pp 468-487. Scriver, pp 3-45. Sack, pp 245-257. Wilson, pp 151-180.) Insertion of one extra nucleotide causes a frame-shift mutation and mistranslation of all the mRNA transcribed from beyond that point in the DNA. All the other mutations cited in the question usually cause an error in the identity of only one amino acid (choice a or b), removal of one amino acid from the sequence (choice d), or no error at all in the amino acid sequence (choice c). There is a chance that the mutations in choices a or b will give a nonsense, or chain-terminator, mutation, and this is about as likely to be lethal as is a frame shift. 

Protein truncation test (PTT) High sensitivity for chain terminating mutations shows position of change Chain-terminating mutations only experimentally difficult best with RNA expensive... 

The protein truncation test is a way of testing large genes (e.g., NEl) for which an antibody is available. PTT can detect nonsense mutations that are peptide chain terminating. These show up, after reverse transcription/cell-free translation, as shorter-than-normal peptides in an electrophoretic gel (Eig. 3C). 

Zidovudine was the first drug of the class. It is a dideoxythymidine analog. It has to be phos-phorylated to the active triphosphate. This triphosphate is a competitive inhibitor of HIV reverse transcriptase. By incorporation into viral DNA it also acts as a chain-terminator of DNA synthesis. Mutations in viral reverse transcriptase are responsible for rapidly occurring resistance. Zidovudine slows disease progression and the occurrence of complications in AIDS patients. It is readily absorbed. However, first pass metabolism reduces its oral bioavailability with some 40%. It readily crosses the blood-brain barrier. Plasma protein binding is about 30%. Zidovudine is glucuronidated in the liver to an inactive metabolite. Its elimination half-life is 1 hour. 

Vidarabine s specific mechanism of action is not fully understood. Cellular enzymes convert this drug to a triphosphate that inhibits DNA polymerase activity. Vidarabine triphosphate competes with deoxyadeno-sine triphosphate (dATP) for access to DNA polymerase and also acts as a chain terminator. Although vidarabine is incorporated into host DNA to some extent, viral DNA polymerase is much more susceptible to inhibition by vidarabine. Vidarabine also inhibits ri-bonucleoside reductase and other enzymes. Resistance occurs as a result of DNA polymerase mutation. 

In the 7 chain, many mutations in the C-terminal portion have been identified, particularly at position 275 (Cote et al, 1998). This residue... 

It has been suggested that the degeneracy of the code minimizes the effects of mutations. Were it not degenerate, 20 codons would specify amino acids and 44 would lead to chain termination, which usually produces inactive proteins. A substitution of one amino acid for another can be benign in many instances, although critical in some instances for normal function (see later). 

Retroviruses like HIV, the pathogen responsible for AIDS, incorporate an RNA template that is copied into DNA during infection. The reverse transcriptase enzyme that copies RNA into DNA is relatively nonselective and error-prone, leading to a high mutation rate. Its lack of selectivity is exploited by the anti-HIV drug AZT (3 -azido-2, 3 -dideoxythymidine), which becomes phosphorylated and is incorporated by reverse transcriptase into DNA, where it acts as a chain terminator. Mammalian DNA polymerases are more selective, having a low affinity for AZT, so its toxicity is relatively low. 

It is of great interest that the Hb-Tak chain is produced in amounts similar to that of most p chain variants. The presence of a threonyl residue in position 147 is unexpected if one assumes that the formation of this p chain is due to a mutation of a terminating codon UAA or UAG. The study of this hemoglobin might well be of importance for a better insight into the mechanism of normal chain termination and in the nature of the DNA between two genes. The presence of Hb-Tak is not associated with any major hematological disorder. 

P-Thalassemia major results from mutations that interfere with translation or are involved in the initiation, elongation, or termination of globin chain synthesis. Mutations that interfere with translation account for almost 50% of ail die p-thalassemia mutations. Included in this are frame shift or nonsense mutations that produce premature termination codons that result in incomplete translation of the P-globin gene and nonproduction of the P-globin chain resulting in P -thalassemia. 

The small insertion/deletion mutations account for about 23% of the nucleic acid sequence alterations that cause disease. An insertion refers to the presence of extra bases while deletion implies the absence of certain bases in comparison to a reference sequence. Insertion and deletion mutations often result in a shift of the codon reading frame, resulting in altered amino acid sequence downstream of the mutation—commonly followed by chain termination from a nonsense codon. Indels are deletions followed by insertions (e.g., replacement of AGGTC by TG). 

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