Codon missense mutation

Figure 38-4. Examples of three types of missense mutations resulting in abnormal hemoglobin chains. The amino acid alterations and possible alterations in the respective codons are indicated. The hemoglobin Hikari p-chain mutation has apparently normal physiologic properties but is electrophoretically altered. Hemoglobin S has a p-chain mutation and partial function hemoglobin S binds oxygen but precipitates when deoxygenated. Hemoglobin M Boston, an a-chain mutation, permits the oxidation of the heme ferrous iron to the ferric state and so will not bind oxygen at all.

Sickle cell anemia is caused by a missense mutation in codon 6 of the P- obin gene. 

Several missense mutations (le, at codons 12, 13, or 61) render the mutant protein Incapable of hydrolyzing bound GTP to GDP. 

Missense mutation The codon containing the changed base may code for a different amino acid. For example, if the serine codon UCA is given a different first base—C—to become CCA, it will code for a different amino acid, in this case, proline. This substitution of an incorrect amino acid is called a "missense" mutation. 

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... 

Altering the nucleotide sequence in a codon can cause silent 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 codon). 

Missense mutation. A change in which a codon for one amino acid is replaced by a codon for another amino acid. 

BSEP also known as sister-P-glycoprotein (SPGP) was originally cloned from pig liver (185). BSEP is localized on the canalicular membrane of hepa-tocytes and is responsible for the secretion of bile salts across the canalicular membrane into bile. BSEP appears to be the predominant bile salt efflux system for hepatocytes, and is a critical component in the enterohepatic circulation of bile acids. A number of mutations in the transporter were found to the basis for progressive familial intrahepatic cholestasis type 2 (PFIC2) (186-188). Mutations found in PFIC2 patients include frameshifts, missense mutations, and premature termination codons. Most PFIC2 patients lack immunohistochemically detectable BSEP in their liver. Recently, seven... 

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)... 

It follows that the technique is useful to identify (1) point mutation (a single different nucleotide) that may be a silent mutation (also known as a synonymous mutation due to degenerate coding), resulting in a codon that codes for the same amino acid or a missense mutation (type of non-synonymous mutation) producing a codon that codes for a different amino acid the resulting protein may be non-functional but certain missense mutations can be quiet since the protein may stiU function polymorphisms, (3) insertions, and deletions. 

In most countries, about one third of the mutations that are identified wfll not have been reported previously in AIP and may represent rare polymorphisms rather than disease-specific mutations. Criteria that suggest that such novel mutations cause disease include production of a frameshift or stop codon, the absence of any other sequence abnormality in the gene, segregation with disease, and nonconservative change of an amino acid residue that is conserved between species and/or known to have a functional role in catalysis. Mutations of consensus bases in splice sites are also likely to be disease specific, but ideally all putative splicing defects should be confirmed by analysis of mRNA. Proof that a missense mutation causes disease may require expression and characterization of the mutant enzyme in a prokaryotic or eukaryotic vector. 

Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, et al. Distinct missense mutations of the FGFR3 Lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet 2000 67 1411-21. 

Functional characterization of missense mutations at codon 838 in retinal guanylate cyclase correlates with disease severity in patients with autosomal dominant cone-rod dystrophy. Hum Mol Genet 9 3065-3073. 

Small-scale mutations include point mutations, which are single nucleotide substitutions, and small deletion and insertion mutations. Point mutations can be further classified into (1) missense mutations, which lead to amino acid change and result in production of abnormal protein, (2) silent mutations, which do not lead to a change in amino acid, and (3) nonsense mutations, in which substitution of a single nucleotide results in formation of a stop codon and a truncated protein. Deletion and insertion mutations result in deletion or insertion of a number of nucleotides that is divisible by 3. This leads to a change in the number of amino acids and a shorter or longer protein, or to an insertion or deletion of a number of nucleotides that is not divisible by 3. This... 

Among the human tumor mutations identified by sequencing, 87.2% are single base substitutions and 12.8% are complex mutations and short deletions or insertions. Missense mutations have been observed at 231 of the 393 codons, including all the codons of the DNA-binding domain except codon 123. This codon (ATC, threonine) is well conserved in evolution, but experimental mutation (to Alanine) at this codon has been shown to activate, rather than suppress DNA-binding activity (Freeman et al., 1994). The vast majority of the mutated codons are recurrent mutation sites that are likely to result in dysfunctional p53. Silent mutations represent up to 3.9% of the mutations in the database and it is possible that mutations occurring at rare... 

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