Sickle Cell Anemia Mutation


J Cleaving the polypeptide allows the fragments to fold into different shapes.


Adding sugars is important for targeting and recognition.


Added phosphate groups alter the shape of the protein.

most polypeptides are modified after translation, and these modifications are essential to the final functioning of the protein (Figure 12.16).

Proteolysis is the cutting of a polypeptide chain. Cleavage of the signal sequence from the growing polypeptide chain in the ER is an example of proteolysis; the protein might move back out of the ER through the membrane channel if the signal sequence were not cut off. Also, some proteins are actually made from polyproteins (long polypeptides) that are cut into final products by enzymes called proteases. Proteases are essential to some viruses, including HIV, because the large viral polyprotein cannot fold properly unless it is cut. Certain drugs used to treat AIDS work by inhibiting the HIV protease, thereby preventing the formation of proteins needed for viral reproduction (see Figure 3.10).

Glycosylation involves the addition of sugars to proteins, as described above. In both the ER and the Golgi apparatus, resident enzymes catalyze the addition of various sugar residues or short sugar chains to certain amino acid R groups on proteins as they pass through. One such type of "sugar coating" is essential for addressing proteins to lyso-somes discussed in the preceding section. Other types are important in the conformation and the recognition functions of proteins at the cell surface. Still other attached sugar residues help in stabilizing proteins stored in storage vacuoles in plant seeds.

Phosphorylation, the addition of phosphate groups to proteins, is catalyzed by protein kinases. The charged phosphate groups change the conformation of targeted proteins, often exposing an active site of an enzyme or a binding site for another protein—as we will see in Chapter 15.

All of the processes we have just described result in a functional protein only if the amino acid sequence of that protein is correct. If the sequence is not correct, cellular dysfunction and disease may result. Changes in the DNA—mutations— are a major source of errors in amino acid sequences.

Mutations: Heritable Changes in Genes

Accurate DNA replication, transcription, and translation all depend on the reliable pairing of complementary bases. Errors occur, though infrequently, in all three processes—least often in DNA replication. But, the consequences of DNA errors are the most severe because only they are heritable.

Mutations are heritable changes in genetic information. In unicellular organisms, any mutations that occur are passed on to the daughter cells when the cell divides. In multicellular organisms, there are two general types of mutations in terms of inheritance:

► Somatic mutations are those that occur in somatic (body) cells. These mutations are passed on to the daughter cells after mitosis, and to the offspring of those cells in turn, but are not passed on to sexually produced offspring. A mutation in a single skin cell, for example, could result in a patch of skin cells, all with the same mutation, but would not be passed on to a person's children.

► Germ line mutations are those that occur in the cells of the germ line—the specialized cells that give rise to gametes. A gamete with the mutation passes it on to a new organism at fertilization.

Very small changes in the genetic material can lead to easily observable changes in the phenotype. Some effects of mutations in humans are readily detectable—dwarfism, for instance, or the presence of more than five fingers on each hand. A mutant genotype in a microorganism may be obvious if, for example, it results in a change in nutritional requirements, as we described for Neurospora earlier (see Figure 12.1).

Other mutations may not be easily observable. In humans, for example, a particular mutation drastically lowers the level of an enzyme called glucose 6-phosphate dehydrogenase that is present in many tissues, including red blood cells. The red blood cells of a person carrying the mutant allele are abnormally sensitive to an antimalarial drug called primaquine;

when such people are treated with this drug, their red blood cells rupture. People with the normal allele have no such problem. Before the drug came into use, no one was aware that such a mutation existed. In bacteria, because of their small sizes and simpler morphologies, distinguishing a mutant from a normal bacterium usually requires sophisticated chemical methods, not just visual inspection.

Some mutations cause their phenotypes only under certain restrictive conditions. They are not detectable under other, permissive conditions. These phenotypes are known as conditional mutants. Many conditional mutants are temperature-sensitive, able to grow normally at a permissive temperature—say, 30°C—but unable to grow at a restrictive temperature—say, 37°C. The mutant allele in such an organism may code for an enzyme with an unstable tertiary structure that is altered at the restrictive temperature.

All mutations are alterations in the nucleotide sequence of DNA. At the molecular level, we can divide mutations into two categories:

► Point mutations are mutations of single base pairs and so are limited to single genes: One allele (usually dominant) becomes another allele (usually recessive) because of an alteration (gain/loss or substitution) of a single nucleotide (which, after DNA replication, becomes a mutant base pair).

► Chromosomal mutations are more extensive alterations than point mutations. They may change the position or orientation of a DNA segment without actually removing any genetic information, or they may cause a segment of DNA to be irretrievably lost.

Point mutations are changes in single nucleotides

Point mutations result from the addition or subtraction of a nucleotide base, or the substitution of one base for another, in the DNA, and hence in the mRNA. Point mutations can be caused by errors in chromosome replication that are not corrected in proofreading or by environmental mutagens such as chemicals and radiation.

Changes in the mRNA may or may not result in changes in the protein. Silent mutations have no effect on the protein; missense and nonsense mutations will result in changes in the protein, some of them drastic.

silent mutations. Because of the redundancy of the genetic code, some point mutations result in no change in amino acids when the altered mRNA is translated; for this reason, they are called silent mutations. For example, there are four mRNA codons that code for proline: CCA, CCC, CCU, and CCG (see Figure 12.5). If the template strand of DNA has the sequence CGG, it will be transcribed to CCG

in mRNA, and proline-charged tRNA will bind to it at the ribosome. But if there is a mutation such that the codon in the template DNA now reads AGG, the mRNA codon will be CCU—the tRNA that binds it will still carry proline:

Base Substitution

Silent mutations are quite common, and they result in genetic diversity that is not expressed as phenotypic differences.

missense mutations. In contrast to silent mutations, some base substitution mutations change the genetic message such that one amino acid substitutes for another in the protein. These changes are called missense mutations:

Missense Mutation Sickle Cell Anemia

A specific example of a missense mutation is the sickle allele for human p-globin. Sickle-cell disease results from a defect in hemoglobin, a protein in human red blood cells that carries oxygen. The sickle allele of the gene that codes for p-globin (one of the polypeptide subunits in hemoglobin; see Figure 3.8) differs from the normal allele by one amino acid in its coding. Persons who are homozygous for this recessive allele have defective red blood cells. Where oxygen is abundant, as in the lungs, the cells are normal in structure and function. But at the low oxygen levels characteristic of working muscles, the red blood cells collapse into the shape of a sickle (Figure 12.17), causing abnormalities in blood circulation that lead to serious illnesses.

Sickle Cell Phenotype

Sickle-cell phenotype

Sickled Red Blood Cells

Normal phenotype

Sickle-cell phenotype

Normal phenotype

12.17 Sickled and Normal Red Blood Cells The misshapen red blood cell on the left is caused by a missense mutation that results in an incorrect amino acid in one of the two polypeptides of hemoglobin.

A missense mutation may cause a protein not to function, but often its effect is only to reduce the functional efficiency of the protein. Therefore, individuals carrying missense mutations may survive, even though the affected protein is essential to life. Through evolution, some missense mutations even improve functional efficiency.

nonsense mutations. Nonsense mutations, another type of mutation in which one base is substituted for another, are more often disruptive than missense mutations. In a nonsense mutation, the base substitution causes a stop codon, such as UAG, to form in the mRNA product:

Insertion Shift Mutation

The result is a shortened protein, since translation does not proceed beyond the point where the mutation occurred. Such short proteins are usually not functional.

frame-shift mutations. Not all point mutations are base substitutions. Single base pairs may be inserted into or deleted from DNA. Such mutations are known as frame-shift mutations because they interfere with the decoding of the genetic message by throwing it out of register:

Frame-shift mutation

Mutation by insertion of T between bases 6 and 7 in DNA

Essentials of Human Physiology

Essentials of Human Physiology

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  • melvin estrada
    Can plasma help a persomn with sickle cell?
    6 years ago

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