Discuss the implications of changes in DNA nucleotide sequence for cell structure and function in Sickle Cell Anemia and Phenylketonuria.

Sumaya Desai (Lower Science IV)

Biology Homework Assignment

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The Deoxyribonucleic acid molecule, which composes the genes of a species, is made up of a long sequence of nucleotides. These nucleotides, taken in a series of three at a time, specify each amino acid subunit on a protein, and consequently the structure of that protein, since the DNA is used to create these in transcription, by using an intermediary mRNA molecule. Changing the sequence of these nucleotide bases in the DNA chain therefore causes a complementary change in the mRNA molecule and the resulting codon and thus the sequence of amino acids in the proteins created in protein synthesis. Such a change in the base sequence of the DNA is known as a genetic mutation. Some genetic mutations are neutral or silent and hence do not affect the protein or the health of the affected individual. However most genetic mutations result in consequent changes in proteins that have a significant effect on the health of the affected individual, as proteins are responsible for most cell activities. A single gene mutation can have many effects if the enzyme it controls is involved in several metabolic processes.

Genetic mutations occur as a result of errors that take place in DNA replication, when the chemical structure of the genes undergoes random modifications. Once such an alteration has taken place, the gene continues to replicate in its changed form, unless another mutation occurs. The usual rate of mutation is low because DNA repair enzymes constantly monitor and repair any irregularities. However mutations may still occur and there are several ways in which they may transpire involving the addition, loss or rearrangement of bases. Figure 1 below shows these different methods. Regardless of how the mutation takes place, all of them result in a change in the nucleotide sequence and subsequently an altered polypeptide chain.

Figure 1 - Different forms of gene mutation, compared to a normal DNA.

These different types of mutations, can be further divided into two groups:

Frameshift mutations
Point mutations

The term reading frame applies to the sequence of codons as these are read from a specific starting point. If one of the bases within one of these codons is deleted, or another inserted, then the reading frame is shifted causing a frameshift mutation. For example if in the following logical sentence, THE CAT HIT THE RAT, the C is deleted, then we read THE ATH ITT HER AT – something that does not make sense. Therefore, if in the normal triplet code ATG TTC GAG TAC, the first thymine base is removed, the ...

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Frameshift mutations
Point mutations

Point mutations result from a change in a single nucleotide base and thus involve only a specific codon. When one base is substituted for another, the results can be variable, see Figure 2. A change in one amino acid may not have an effect if the change occurs in a noncritical area or if the two amino acids have the same properties.

Figure 2 – Point Mutation. The effect of base alteration varies. The base change may still code for the same amino acid, resulting in no noticeable effect. However if the base change, codes for a stop codon, the created protein will be incomplete, and if the base change codes for a different amino acid, a faulty protein will be possible.

The effects of gene mutations are variable. Some may pass unnoticed in the phenotype since they are recessive, but they may also have a profound effect. Gene mutations may cause the building of defective protein molecules that are unable to effectively carry out their functions, causing genetic disorders such as sickle cell anemia and phenylketonuria

Sickle cell anemia is the most common inherited blood disorder in the United States. It is a genetic disorder of the blood, which is caused by a defective gene that produces an abnormal form of hemoglobin, hemoglobin S (HbS) instead of normal adult hemoglobin, HbA. Hemoglobin is the protein component of red blood cells, which is responsible for carrying the oxygen required for cellular respiration to all the body tissue from the lungs. It is composed of two -chains with 141 amino acids and two -chains with 146 amino acids. Sickle cell anemia occurs when a transversion point mutation on chromosome 11 of the DNA causes the amino acid valine to replace glutamic acid in the sixth position of the polypeptide chains of hemoglobin (See Figure 3 below). Although the -polypeptide chain is 146 amino acids long, this one change causes sickle cell anemia.

Figure 3 – Portion of the normal hemoglobin chain in which the mutation takes place compared to the corresponding area in hemoglobin chain causing sickle cell anemia.

The codon for glutamic acid is GAG, which corresponds to the triplet CTC in the DNA sense strand. If this triplet is changed to CAC, the codon on the mRNA becomes GUG, which is the codon for valine, causing this amino acid to be produced instead. Glutamate has a polar R group, while valine has a non-polar one, and this cause HbS to be less soluble and to precipitate out of soloution, distorting the biconcave red blood cells into a hard, sticky sickle shape, when it is deoxygenated.

Sickle cell anemia is an inherited disorder, which is incompletely dominant. It is only obtained if both parents are carriers or suffer from the disease. A normal person inherits two alleles - one from each parent – and each containing genetic information for HbA. Persons who have sickle cell anemia obtained the alleles, HbS and HbS. Those who have one of each i.e. HbA and HbS genotype are carriers of the disease, having the sickle cell trait and the ability to pass it onto their children, but not acquiring its symptoms. Two persons with the sickle cell trait can have children with all three phenotypes (see Figure 4 on the following page). If an affected person and a carrier conceive, there is a 50% chance that their child will have the disorder.

Figure 4: Genetic diagram showing possible children of (A) two persons with the sickle cell trait and (B) An infected person and a carrier.

Since sickle-shaped cells cannot pass through narrow capillary passageways, like their disk-shaped counterparts; they clog these vessels and break down. This causes a person suffering sickle cell anemia to have poor circulation, anemia and poor resistance to infection. Normal red blood cells have a 120-day life span, but sickle shaped ones usually have no more than 20 days. When the bone marrow production of red blood cells cannot keep up with the sickle blood cell lost, symptoms of anemia develop. Most people with sickle cell disease have at least mild symptoms of chronic anemia, which include

Weakness
Constant Fatigue
Pale appearance
Yellowing of the skin and the whites of the eyes – jaundice
Shortness of breath, particularly with exertion

Such symptoms may make it difficult for them to manage their daily routine. Rapid breakdown of the red blood cells also increase the risk of obtaining gallstones.

Because sickle cells are likely to get trapped in vessels throughout the body, blood flow may become blocked. This results in a reduced blood flow that may damage the body’s organs, as these may be deprived of oxygen, and this damage could lead to life-threatening conditions. Blocked blood flow to the brain may cause a sudden stroke or cognitive impairment (silent brain damage). Blood flow to the bones may also be impeded and this could result in osteonecrosis (bone and joint damage) and may even cause hand and feet deformities. Areas where blood vessels are blocked can become extremely painful. These painful events (vaso-occulation) are one of the most common and difficult problems caused by sickle cell disease.

Sickle cell disease may also cause poor growth and eye damage, due to the blocking of the blood flow in the inner lining of the eye (retina). People with sickle cell anemia also have a higher rate of attaining certain infections, since they have a lower resistance to diseases.

Like sickle cell anemia, phenylketonuria (PKU) is another genetic disorder that is caused by a transversion mutation. It is a rare recessive disorder that occurs once in every 5, 000 live births, but is the most common inherited metabolic disorder to affect the nervous system development. The PKU gene is located on chromosome 12 of the DNA and enables the conversion of the essential amino acid phenylalanine to the amino acid tyrosine through the production of the enzyme phenyalanine hydroxylase, which catalyses this reaction.

Children suffering from the disease appear normal at birth as the mother’s liver takes care of this reaction for the developing foetus. However, after birth phenylaline begins to accumulate in the blood as affected individuals lack the ability to accurately manufacture this enzyme. Due to their ineffective or inactive enzyme, the level of phenylaline in the body gradually increases, causing it to reach a toxic level that become detrimental to health. Some of the pheylaline may be converted into phenylpyruvic acid and excreted in the urine. However, most remain and the excess phenylaline prevents the child’s brain from absorbing sufficient amounts of other essential amino acids from the blood. This results in the failure of the brain and other organs and tissues such as muscles and cartilage to grow and develop normally. Consequently, if the condition is untreated, the infant’s developing nervous system is damaged and other harmful effects, such as severe mental retardation, as well as other neurological problems are attain. These other effects, which vary from individual to individual include:

Hyperactivity and irritability
Peculiarities of gait, stance and sitting posture
Lighter skin pigmentation and fair hair (as excess phenyalanine usually inhibits the synthesis of the skin pigment melanin that provides skin and hair with their color)
Musty odor of sweat and urine due to the presence of phenylketones
Dry, rough skin (eczema)
Repetitive movements of the fingers, hands or entire body
Convulsions due to irregular activity of the brain (epilepsy)

PKU is an “autosomal recessive” gene. This means that, like sickle cell anemia, in order for there be any chance that a child will acquire the disorder, both parents must either be silent carriers or affected individuals. Two carriers have a 25% chance of attaining a child with the disease with each pregnancy, whilst a carrier and an infected person have a 50% chance of having both an infected child and the same likelihood of having a child who is a carrier. The disastrous effects of the disorder may be avoided by consuming a diet that is devoid of phenylaline.

A seemingly insignificant random change in the nucleotide sequence of the DNA caused through an error that occurred in DNA replication, may result in genetic disorders, such as sickle cell anemia and phynelketonuria. These disorders can have widespread and notable implications on the life of those who suffer from it, making life very uncomfortable for them and affecting numerous parts of their body.