Sickle Cell Disease And Human Genotype Biology

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Human genotype is the most outstanding determinant of human pathogenesis. Thus, the function of human cistron on the patterned advance and development of human disease can never be neglected. A familial disorder might be monogenetic which occurs due to a mutation in a particular gene. For example, sickle cell disease, thalassemia, and cystic fibrosis are the illustrations of monogenetic disorders caused due to a defect in a specific genetic mutation. In contrast, in some familial disorders, mutations occur in more than one gene causing the same disease. Thus Alzheimer’s disease and Parkinson’s disease which are caused due to the involvement of more than one gene can be termed as multigenic diseases.

Sickle Cell Disease is a monogenetic disorder in hemoglobin causing the Red Blood Cells (RBC) to form an unnatural sickle shape. This process is called sickling which eventually results in the loss of flexibility in RBC and other infectious effects. The factor involved behind the sickling of RBC is the mutation of Beta Globin gene located on chromosome 11.

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This disorder is prevalent in people originated from tropical and subtropical regions where malaria was common. About one-third of the indigenous people of Sub-Saharan Africa bear this mutated Beta globin gene. Sickle cell disease results in decreased life expectancy with the mean life of males and females being 42 years and 48 years in affected males and females, respectively (Platt OS, et al., 1994).


A point mutation in the Beta-globin gene of chromosome 11, which results in the substitution of hydrophilic glutamic acid to hydrophobic valine at the 6th position, gives rise to the mutated beta hemoglobin subunit. When two mutated beta hemoglobin subunits bind to two wild-type alpha subunits, formation of an aberrant hemoglobin called HbS takes place. Being benign in nature, this mutation does not cause any evident effects on the secondary, tertiary, or quaternary structure of hemoglobin under normal oxygen concentration.

However, this HbS has a tendency to polymerize in low-oxygen tension and causes polymerization of the hemoglobin. In this process, the hydrophobic residues of valine at position 6 of the beta chain of HbS associates with the hydrophobic spot, causing the hemoglobin molecules to aggregate and form fibrous precipitates. The recurrent episodes of polymerization and sickling cause lasting malformation on the shape of RBC and decreased elasticity.

When these deformed and stiff RBCs pass through the capillaries, they get occluded there due to decreased elasticity. Thus, the adhesion of unnatural red blood cells (RBC) to the endothelium has been proposed as the likely initiating event of vasoocclusion. However, the fluctuations in the endothelium activation state may modulate the unpredictable happening of the major complications (Hebbel RP, 1997). Inflammation is the major catalytic agent for this process (Kaul DK, Hebbel RP, 2000). This process ultimately results in ischemia.

The anemia in sickle cell disease is caused by hemolysis due to the destruction of the RBCs inside the spleen. The rapid destruction rate of RBCs exceeds the rate of refilling rate of bone marrow. Unlike healthy red blood cells, typically sickle cells survive merely for 10-20 days. Though the peripheral destruction of sickled RBCs has been considered to be an outstanding characteristic of sickle cell disease, the possible role of ineffective erythropoiesis in the pathophysiology of this hemoglobinopathy is also a point to be considered. (Catherine J. Wu et al., 2005).


Dietary cyanate or derivatives can be used in the treatment of sickle cell disease. Painful crisis due to vaso-occlusion can be managed by analgesics, opioid administration. Children born with sickle cell disease are given a 1 milligram dosage of folic acid per day throughout their life. As a supplement, they are also given a dosage of penicillin until the age of five years to safeguard against infections. In adult patients with acute chest pain due to vaso-occlusion, oxygen supplementation and blood transfusion can provide relief. Bone marrow organ transplant has been found to be effective in children. (Walters MC, Patience M, Leisenring W, et al., 1996).

Hydroxyurea is the first sanctioned drug for the treatment of sickle cell anemia which has successfully decreased the severity of attacks in a study done by Charache et al. in 1995. “To date, hydroxyurea (HU) is the only drug known to reduce the frequency of vasoocclusive crises, acute chest syndromes (ACSs), and transfusion demands.” (Malika Benkerrou et al., 2002). The possible mechanism of action of hydroxyurea has been believed to be the reactivation of fetal hemoglobin in place of HbS. Nevertheless, the long-term usage of this drug as a chemotherapeutic agent has shown some risks. (Platt OS, 2008).

Gene therapy is the most recent and most promising technique for the treatment of monogenic disorders like sickle cell disease.

Alzheimer’s disease (AD)

Alzheimer’s disease (AD) was named after German psychiatrist Alois Alzheimer who first described it in 1906 as an incurable, neurodegenerative disease generally diagnosed in people over 65 years of age. The report of September 2009 shows that the number of patients suffering from Alzheimer’s disease worldwide is more than 35 million. This prevalence has been expected to reach up to 107 million by 2050. (Brookmeyer, R et al., 2007).

Alzheimer’s disease is a type of protein misfolding disease (proteopathy), caused by the accumulation of abnormally folded amyloid-beta and tau proteins in the encephalon. Hence, it is also called a tauopathy due to an unnatural collection of the tau protein in the brain.

The clinical picture of AD is variable; nevertheless, the common characteristic is progressive dislocation of memory and cognitive maps like reasoning (Nussbaum et al 2004). Confusion, irritability, language dislocation, aggression, and long-term memory loss are some of the symptoms that appear as the disease becomes more severe. This finally leads to the loss of body functions and death. Most AD patients are expected to survive for around seven years after getting diagnosed. However, less than 3% of patients remain alive even after 14 years of diagnosis.


AD is chiefly a sporadic disease, and only 0.1% of cases are familial, which onset before the age of 65. Nevertheless, some genes act as a risk factor (Blennow K, de Leon MJ, Zetterberg H, 2006). Most of the familial autosomal dominant AD is due to a mutation in one of the following genes:

  1. APP (Amyloid precursor protein) gene,
  2. presenilin1, and
  3. Presinilin2

Most of the mutations in APP or Presenilin give rise to the production of AB42 (Amyloid beta 42), which is the major portion of senile plaques seen in AD.

Apolipoprotein E (APOE) is another familial factor associated with AD. APOE is a common amino acid involved in cholesterol transport. However, it is also detected in both plaques and neurofibrillary tangles associated with AD. Studies have shown that at least 40 to 80 percent of persons with AD possess at least one APOE 4 allele.

Though the exact cause of the onset of AD has not yet been revealed, some theories have been put forward. They are:

  1. Cholinergic hypothesis,
  2. Amyloid Hypothesis, and
  3. Tau Hypothesis.

The cholinergic hypothesis says that impaired synthesis of a neurotransmitter called acetylcholine is responsible for the onset of AD (Francis PT, Palmer AM, Snape M, Wilcock GK, 1999). However, this hypothesis was refuted by the evidence that medicines intended to treat acetylcholine lack could not produce promising results.

Starchlike hypothesis holds the impression that deposition of starchy beta protein (ABP) derived from starchy beta precursor protein (APP) is the main basis of the AD. This APP is encoded by the APP gene located on chromosome 21.

According to this hypothesis, the plaques of AD are made up of small A peptides called beta-amyloid. Beta-amyloid is derived from a larger protein called amyloid precursor protein (APP), which penetrates through the nerve cell’s membrane. APP has an important function in neuron growth, endurance, and post-injury repair.

In Alzheimer’s disease, APP is divided into smaller fragments by enzymes through proteolysis. Fibrils of beta-amyloid are derived from one of these fragments of APP. These filaments then form bunches. These clump sediments outside nerve cells are known as senile plaques. The fibrils thus formed disrupt the cell’s Ca ion homeostasis. This procedure eventually results in programmed cell death. (Yankner BA, Duffy LK, Kirschner DA, 1990)

In 2004, the Tau hypothesis for AD emerged when the amyloid hypothesis was challenged by the fact that amyloid plaques do not correlate with the neuron loss. (Schmitz C, Rutten BP, Pielen A, et al., 2004). The Tau hypothesis emphasizes that when hyperphosphorylated Tau braces with other yarn of Tau, formation of a neurofibrillary tangle takes place inside the nerve cell bodies.

As we know, every nerve cell has a cytoskeleton, partially made up of microtubules, which help in guiding different molecules from the body of the cell to the terminals of the axon. The Tau hypothesis says that tau protein stabilizes the microtubules when phosphorylated and undergoes chemical alterations, becoming hyperphosphorylated. After that, tau protein braces with other togss and creates neurofibrillary tangles. This procedure disintegrates the nerve cell’s conveyance system. (Hernandez F, Avila J, 2007). As a result, biochemical communication stops between the nerve cells leading to cell death.


Since Alzheimer’s disease does not have any cure so far, only diagnostic treatment can be given to the sick individuals. AD can be managed by the following aspects:

  1. Pharmaceutical
  2. Acetylcholinesterase inhibitors are used to reduce the rate of acetylcholine broken down.
  3. Glutamate, which is a useful excitatory neurotransmitter of the nervous system.
  4. Memantine (trade name names Akatinol, Axura, Ebixa/Abixa, Memox, and Namenda), is a noncompetitive NMDA receptor antagonist.
  5. Antipsychotic drugs can be used to reduce aggression and psychosis in Alzheimer’s patients with behavioral problems.
  6. Psychosocial interventions
  7. Psychosocial intervention is complementary to pharmaceutical intervention in AD patients. Especially dementia is managed by psychosocial intervention.
  8. Caregiving

Since AD renders people incapable of fulfilling their own needs, caregiving is very indispensable.

Comparative overwiev of Sickle Cell Disease and Alzheimer’s Disease

Sickle cell disease (SCD) is a genetic disorder caused by a mutation of the beta hemoglobin gene on chromosome 11, resulting in the substitution of glutamic acid by valine, whereas Alzheimer’s disease (AD) is a multigenic disease caused by mutations in multiple genes such as beta APP, PS1, PS2, and APOE. SCD is a purely genetic disorder, whereas AD is very rarely genetic.

Both of these disorders involve changes in the structure of proteins. However, SCD is basically a hemoglobinopathy due to the polymerization of abnormally synthesized hemoglobin. In contrast, AD arises from the accumulation of beta-amyloid peptide in the brain, leading to cognitive abnormalities and degeneration of nerve cells.

In cystic fibrosis (CF), mutation leads to an upset ubiquitin-proteasome pathway that leads to protein accumulation resulting in the disease. Antibiotics and gene therapy help to some extent in CF; if not, lung transplant is the end-stage therapy used, which helps to extend the lifespan by a few years because lungs are the most affected organs.

In Alzheimer’s, the brain is the affected organ, and antidementia drugs such as memantine and donepezil are used, and a good diet and exercise also play an important role in reducing the risk of the disease. Although both are protein misfolding diseases, there are many dissimilarities between them, as mentioned above. CF occurs in all age groups (newborns, children, adults, elderly people), but Alzheimer’s mostly occurs in elderly people; therefore, CF is a more dangerous disease than Alzheimer’s.

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Sickle Cell Disease And Human Genotype Biology. (2016, Dec 07). Retrieved from

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