Pathogenic mutations


Critically compare and contrast, a non-cancerous hereditary disease, which is caused by a single gene (monogenetic) defect (e.g. thalassemia or cystic fibrosis, Huntington’s chorea) to a common non-cancerous disease (e.g. Alzheimer’s or Parkinson’s) that has a multigenic component (more than one gene can cause or predispose individuals to the same disease). Your answer should cover the following points: a) Identify the gene, in the case of the chosen monogenetic disease or several (at least 3) of the genes involved in causing or predisposing individuals to suffering from your chosen common multigenic disorder b) The pathogenic mutations involved that cause or predispose to these diseases c) How do these mutations affect the proteins and downstream pathways involved in these diseases? d) What therapies have been devised to treat or potentially treat these diseases?

A minimum of 5 recent papers (the majority from 2005-2009) must be used. Because these questions are not individualised for separate students, you should take particular care to ensure that your answer is entirely your own work: naturally it is imperative that you do not collude in any way with fellow students in preparing your answer, to avoid ‘academic deceit’. Finally, submission size is not strictly determined for these questions; rather, conciseness is valued: but around 3 sides of A4 (including diagrams and bibliography) are likely to be the minimum required to do justice to these questions.

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Human genotype is the most prominent determinant of human pathogenesis. Thus the role of human gene on the progression and development of human disease can not be neglected. A herediatery disorder might be monogenetic which occurs due to mutation in a single particular gene.For instance sickle cell disease, thalassemia, Cystic fibrosis are the examples of monogenetic disorder which are caused due to defect in a particular genetic mutation. In contrast, in some genetic disorders, mutation occurs in more than one gene causing the same disease. Thus Alzheimer’s disease and prkinson’s disease which are caused due to involvement of more than one gene can be termed as multigenic diseases.

Sickle Cell Disease (SCD)


Sickle Cell Disease which is a monogenetic heamoglobinopathy causing the Red Blood Cells(RBC) to form an abnormal sickle shape.This process is called sickling which ultimately results in the loss of flexibility in RBC and other pathogenic consequencs. The factor involved behind the sickling of RBC is the mutation of Beta Globin gene located in chromosome 11. This disorder is prevalent in people who originated from tropical and sub tropical regions where malaria is /was common. Nearly one third indigenous pople of Sub- Saharan Africa bear this mutated Beta globin gene. Sickle cell disease results into reduced life expectancy with average life of male and female being 42 years and 48 years respectively in affected males and females respectively. (Platt OS, et al, 1994)


A point mutation in the β-globin gene of chromosome 11 , which results in the substitution of hydrophilic glutamic acid to by hydrophobic valine at the sixth position gives rise to mutated beta globin sub unit.When two mutated beta globin subunits bind to two wild type alpha sub units, formation of a an abberent haemoglobin called HbS takes place. Being benign in nature, this mutation does not cause any apparent effects on the secondary, tertiary, or quaternary structure of haemoglobin in conditions of normal oxygen concentration. However, this HbS has a tendency to polymerize in low-oxygen tension and causes polymerisation of the haemoglobin. In this process, the hydrophobic residues of the valine at position 6 of the beta chain of HbS associates with the hydrophobic patch, making the haemoglobin molecules to aggregate and form fibrous precipitates. The repeated episodes of polymerization and sickling causes permanent deformity on the shape of RBC and decreased elasticity. When these deformed and rigid RBCs pass through the capillaries, they get occluded there due to reduced elasticity. Thus the adhesion of abnormal red blood cell (RBC) to the endothelium has been proposed as the probable initiating event of vasoocclusion, nevertheless the variations in the endothelium activation state may modulate the unpredictable occurrence 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 ischaemia.

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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 RBC exceeds the rate of replenishment rate of bone marrow. Unlike healthy red blood cells typically sickle cells survive only for 10-20 days.Though the peripheral destruction of sickled RBCs have been considered to be prominent feature of sickle cell disease, potential contribution of ineffective erythropoiesis to the pathophysiology of this hemoglobinopathy is also point to be considered. (Catherine J. Wu et al,2005).


Dietary cyanate or derivatives can be used on the treatment of sickle cell disease. Painful crisis due to vaso-occlusion can be managed by analgesics, opoid administration.Children born with sicle cell disease are given 1 mg dose of folic acid per day throughout the life. As a supplement they are accompanied by a dose of penicillin too, till the age of five years in order to safe guard from infections. In adults patients with acute chest pain due to vaso-occlusion, oxygen supplementation, and blood transfusion can give relief. Bone marrow transplantation has been found to be effective in children. (Walters MC, Patience M, Leisenring W, et al., 1996)

Hydroxyurea is the first approved drug for the treatment of sickle cell anemia which had 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 requirements”. (Malika Benkerrou et al, 2002). The possible mechanism of action of hydroxyurea has been believed to be the reactivation of fetal heamoglobin in place of HbS. Neverthless the long term use of this drug as a chemotheraupetic agent has shown some risks. ( Platt OS, 2008).

Gene therapy is the most novel and most promising technique for treatment of monogenetic disorder 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 a incurable , neurodegenerative disease generally diagnosed in people more than 65 years of age.( Brookmeyer R, Gray S, Kawas C, 1998). The survey of September 2009 shows that 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 a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded amyloid-beta and tau proteins in the brain. Hence it is also called a tauopathy due to abnormal aggregation of the tau protein in brain.

The clinical picture of AD is variable , however the common feature is progressive breakdown of memory and cognitive functions like reasoning.(Nussbaum et al 2004). Confusion, irritability , language breakdown, aggression and long term memory loss are some of the symptoms that appear as the disease becomes more severe.( Waldemar G, et al. 2007)( Tabert MH et al 2005).This ultimately leads to loss of body functions and death. Most of the AD sufferers, are expected to survive for around seven years after getting diagnosed..( Mölsä PK, Marttila RJ, Rinne UK , 1986.).However, less than 3%sufferers remain alive even after fourteen years of diagnosis. (Mölsä PK, Marttila RJ, Rinne UK 1995)


AD is mainly a sporadic disease and only 0.1 percent cases are familial which onst before the age of 65. Neverthless there are some genes that act as a risk factor. (c Blennow K, de Leon MJ, Zetterberg H (July 2006). "Alzheimer's disease". Lancet 368 (9533): 387-403). Most of the familial autosomal dominant AD are due to mutation in one of the following genes: 1)APP (Amyloid precursor protein) gene 2)presenilin1 and 3)Presinilin 2 (Waring SC, Rosenberg RN (March 2008).

"Genome-wide association studies in Alzheimer disease". Arch Neurol 65 (3): 329-34). Most of the mutation in APP or Presenilin gives rise to the production of AB42(Amyloid beta 42) which is the major part of senile plaques that are seen in AD.

Apolipoprotein E(APOE) another genetic factor associated with AD. APOE is actually a common aminoacid involved in cholesterol transport. However it is also detected in both plaques and neurofibraillary tangles associated with AD.Studies have shown that at least 40 to 80 percent individuals with AD possess at least one APOE 4 allele.( Mahley RW, Weisgraber KH, Huang Y (April 2006). "Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease". Proc. Natl. Acad. Sci. U.S.A. 103 (15): 5644-51)


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

i)Cholinergic hypothesis

ii)Amyloid Hypothesis and

iii)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 medications intended to treat acetylcholine deficiency could not produce promising results.

Amyloid hypothesis holds the notion that deposition of amyloid beta protein (ABP) derived from amyloid beta precursor protein(APP) is the main basis of the AD.( Hardy J, Allsop D ,1991 )( Mudher A, Lovestone S , 2002). This APP is encoded by APP gene located on chromosome 21.

According to this hypothesis, the plaques of AD are made up of small peptides, 39-43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair.[55][56] In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes throughproteolysis.[57] One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques.[12][58]

These fibrils disrupt the cell’s calcioum ion homeostasis . This process ultimately results in programmed cell death or apoptosis.( Yankner BA, Duffy LK, Kirschner DA (October 1990). "Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides". Science (journal) 250 (4978): 279-82.)

In 2004, Tau hypothsis for AD emerged when 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. (April 2004). "Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's diseaseTau hypothesis emphasize that when hyperphosphorylated Tau pairs with other thread of Tau, formation of a neurofibrillary tangle takes place inside the nerve cell bodies. Goedert M, Spillantini MG, Crowther RA (July 1991). "Tau proteins and neurofibrillary degeneration". Brain Pathol 1 (4): 279-86. doi:10.1111/j.1750-3639.1991.tb00671.x
As we know every neuron has a cytoskeleton, partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. The Tau hypothesis says that tau protein stabilizes the microtubules when phosphorylated and undergoes chemical changes, becoming hyperphosphorylated. It then begins to pair with other threads, creating neurofibrillary tangles and disintegrate the neuron's transport system. ( Hernández F, Avila J (September 2007). "Tauopathies". Cell. Mol. Life Sci. 64 (17): 2219-33).

As a result, biochemical communication stops between theneurons leading to death of cell.


Since there is no cure available for Alzheimer's disease; only symptomatic treatment can be given to the sufferers. The treatment can be divided into pharmaceutical, psychosocial and caregiving.


1. Acetylcholinesterase inhibitors are used to reduce the rate of acetylcholine broken down.
2. Glutamate which is a useful excitatory neurotransmitter of the nervous system.
3. Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda),[142] is a noncompetitive NMDA receptor antagonist
4. Antipsychotic drugs can be used to reduce aggression and psychosis in Alzheimer's patients with behavioural problems

Psychosocial interventions

Psychosocial intervention is complementary to pharmaceutical treatment in AD patients. Especially dementia is managed by psychosocial intervention.


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


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Catherine J. Wu et al, 2005. RED CELLS: Evidence for ineffective erythropoiesis in severe sickle cell disease, Blood | 2005-11106: | 3639 - 3645

Charache S, et al,1995. "Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia". N. Engl. J. Med. 332(20): 1317-22

Hebbel RP, 1997. Adhesive interactions of sickle erythrocytes with endothelium. J Clin Invest.;99:2561-2564

Kaul DK, Hebbel RP,2000. Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. J Clin Invest.106:411-420

Walters MC, Patience M, Leisenring W, et al., 1996. Bone marrow transplantation for sickle cell disease. N. Engl. J. Med. 335 (6): 369-76

Malika Benkerrou et al, 2002. CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS: Hydroxyurea corrects the dysregulated L-selectin expression and increased H2O2 production of polymorphonuclear neutrophils from patients with sickle cell anemia
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Platt OS, 2008. "Hydroxyurea for the treatment of sickle cell anemia". N. Engl. J. Med. 358 (13): 1362-9

Brookmeyer R, Gray S, Kawas C, 1998. "Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset". Am J Public Health 88 (9): 1337-42

Brookmeyer, R et al ,2007. "Forecasting the global burden of Alzheimer’s disease". Alzheimer's and Dementia 3 (3): 186-91

Nussbaum et al ,2004. Thompson and Thompson Genetics in medicine. 6th edition, revised.Pennsylvania: Saunders

Waldemar G et al. 2007. "Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline". Eur J Neurol 14 (1): e1-26. doi:10.1111/j.1468-1331.2006.01605.x

Tabert MH et al 2005. "A 10-item smell identification scale related to risk for Alzheimer's disease". Ann. Neurol. 58 (1): 155-160.doi:10.1002/ana.20533. PMID 15984022.

Mölsä PK, Marttila RJ, Rinne UK , 1986. "Survival and cause of death in Alzheimer's disease and multi-infarct dementia". Acta Neurol Scand 74 (2): 103-7

c Mölsä PK, Marttila RJ, Rinne UK 1995). "Long-term survival and predictors of mortality in Alzheimer's disease and multi-infarct dementia". ActaNeurol Scand 91 (3): 159-64

Van Broeck B, Van Broeckhoven C, Kumar-Singh S ,2007. "Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches". Neurodegener Dis 4 (5): 349-65

Francis PT, Palmer AM, Snape M, Wilcock GK, 1999. "The cholinergic hypothesis of Alzheimer's disease: a review of progress". J. Neurol. Neurosurg. Psychiatr. 66 (2): 137-47

Hardy J, Allsop D ,1991. "Amyloid deposition as the central event in the aetiology of Alzheimer's disease". Trends Pharmacol. Sci. 12 (10): 383-88. doi:10.1016/0165-6147(91)90609-V. PMID 1763432.

Mudher A, Lovestone S , 2002. "Alzheimer's disease-do tauists and baptists finally shake hands?". Trends Neurosci. 25 (1): 22-26. doi:10.1016/S0166-2236(00)02031-2. PMID 11801334

c Blennow K, de Leon MJ, Zetterberg H (July 2006). "Alzheimer's disease". Lancet 368 (9533): 387-403

Waring SC, Rosenberg RN (March 2008). "Genome-wide association studies in Alzheimer disease". Arch Neurol 65 (3): 329-34

Mahley RW, Weisgraber KH, Huang Y (April 2006). "Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease". Proc. Natl. Acad. Sci. U.S.A. 103 (15): 5644-51

Yankner BA, Duffy LK, Kirschner DA (October 1990). "Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides". Science (journal) 250 (4978): 279-82.

Schmitz C, Rutten BP, Pielen A, et al. (April 2004). "Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease". Am J Pathol 164 (4): 1495-1502. PMID 15039236.

^ Goedert M, Spillantini MG, Crowther RA (July 1991). "Tau proteins and neurofibrillary degeneration". Brain Pathol 1 (4): 279-86. doi:10.1111/j.1750-3639.1991.tb00671.x. PMID 1669718.

^ Iqbal K, Alonso Adel C, Chen S, et al. (January 2005). "Tau pathology in Alzheimer disease and other tauopathies". Biochim Biophys Acta 1739 (2-3): 198-210. doi:10.1016/j.bbadis.2004.09.008. PMID 15615638.

^ Chun W, Johnson GV (2007). "The role of tau phosphorylation and cleavage in neuronal cell death". Front Biosci 12: 733-56.
Hernández F, Avila J (September 2007). "Tauopathies". Cell. Mol. Life Sci. 64 (17): 2219-33. doi:10.1007/s00018-007-7220-x. PMID 17604998.