Nonsense mutations, protein

Point mutations Protein folding Transcriptional control Frameshiftand nonsense mutations RNA processing Sickle cell disease P-Thalassemia P-Thalassemia P-Thalassemia... 

A naturally occurring animal model of PFK-M deficiency has been reported in English springer spaniels. Molecular analysis of this canine PFK-M deficiency disclosed that the enzyme deficiency was caused by a nonsense mutation in the penultimate exon of the PFK-M gene, leading to rapid degradation of a truncated (40 amino acid residues) and therefore unstable enzyme protein (SI8). 

Nonsense mutation A nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all. 

Different mutations in the disease-causing locus may cause more or less severe expression. For example, mis-sense mutations in the factor VIII gene tend to produce less severe hemophQia than do nonsense mutations, which result in a truncated protein product and little, if any, expression of factor VIII. The presence of different mutations, or alleles, in the same locus is termed allelic heterc eneity. 

A variety of AVPR2 nonsense mutations causes the most severely affected NDI phenotypes (121). Although truncation frequently occurs within TM domain 3, severe phenotypes have also been reported as a consequence of the Argl37His mutation. The Argl37His mutation is representative of variant receptors that are unable to activate stimulatory Gs proteins (122). The receptor fails to respond to agonist through stimulated adenylyl cyclase activity. Many other A VW 2 mutations, such as frame-shift and small in-frame deletions, also result in AVPR2s that fail to couple to G a (123). 

Protein synthesis inhibition—prokaryotes Protein synthesis inhibition—eukaryotes Mistranslation on ribosomes Nonsense mutation suppression DNA translation Phenotypic suppression Membrane leakiness Nucleic acid binding/precipitation... 

The answer is C. Production of a truncated protein indicates that a mutation has occurred, but this phenomenon may have arisen from a frameshift mutation (insertion or deletion) or by a nonsense mutation. The most likely possibility is a nonsense mutation because sequence analysis of the truncated protein showed that it had normal (wild-type) sequence. Insertion and deletion events often produce a stretch of garbled or abnormal protein sequence at the C-terminal end of the truncated protein arising from out-of-frame translation of the mRNA downstream of the mutation until a stop codon is encountered. 

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). 

Codons are composed of three nucleotide bases usually presented in Ihe mRNA language of A, G, C, and U. They are always written 5 —>3. Of the 64 possible three-base combinations, 61 code for the twenty common amino acids and three signal termination of protein synthesis (translation). Altering the nucleotide sequence in a codon can cause sient mutations (the altered codon also codes for the original amino acid), missense mutations (the altered codon codes for a different amino acid), or nonsense mutations (the altered codon is a termination... 

MISSENSE MUTATION A mutation that changes one codon into another, leading to incorporation of a different amino acid in protein synthesis and sometimes resulting in an inactive protein. (See also NONSENSE MUTATION)... 

Subsequently, serum lipid and lipoprotein profiles were obtained 70 mg/dL total cholesterol (normal is 130-200 mg/dL), 1 mg/dL HDL cholesterol (optimal is > 60 mg/dL), 180 mg/dL triglycerides (normal is 100-150 mg/dL), and less than 5 mg/dL apolipoprotein A-I (apoA-I normal is 140 mg/dL). Cholesterol efflux from patient skin fibroblasts to apoA-I, the main protein component of HDL, was reduced to 30% of normal. These results indicated Tangier disease, the definitive diagnosis of which was made when the sequencing of the ATP-binding cassette transporter A1 (ABCA /) gene revealed a nonsense mutation within exon 12. 

Four classes of LDL receptor mutations have been identified. Class 1 mutations are characterized by the failure of expression of the receptor protein. It is possible, however, that a modified protein is produced but it is not recognized as an LDL receptor protein. Class 2 mutations involve a nonsense mutation (premature termination of protein synthesis Chap. 17), and result in a defect in the transfer of the receptor from the endoplasmic reticulum to the cell membranes. This class of mutation is common in Afrikaners and Lebanese. The Watanabe heritable hyperlipidemic rabbit (WHHL) is an animal model which has a Class 2 defect and has been used extensively for the study of familial hypercholesterolemia. Class 3 mutations result in abnormal binding of LDL. This can be caused by alterations in the amino acid sequence of Domain 1. Class 4 mutations are those with defective internalization due to the receptor s inability to be located in coated pits. This is the result of mutations in the fifth, C-terminal domain. 

Nonsense Mutation. A base substitution that mutates the codon of one amino acid to a stop codon, TAA (ochre), TAG (amber), or TGA (opal). A nonsense mutation results in protein truncation of a protein-coding gene. Thus, nonsense mutation is another type of severe mutation, which results in inactivation of the protein product most of the time. 

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