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Sickle-cell disease When one of the genes on chromosome 11 that codes for haemoglobin undergoes a substitution. It beco...

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Sickle-cell disease

When one of the genes on chromosome 11 that codes for haemoglobin undergoes a substitution. It becomes expressed as an unusual form of haemoglobin called haemoglobin S. this is an example of missense. Although haemoglobin S differs from normal haemoglobin by only one amino acid, that one tiny alteration leads to profound changes in the folding and the ultimate shape of the haemoglobin S molecule, making it a very inefficient carrier of oxygen.

People who are homozygous for the mutant allele suffer drastic consequences. In addition to all of their haemoglobin being type S, which fails to perform the normal function properly, sufferers also possess distorted, sickle-shaped red blood cells. These are less flexible than the normal type and tend to stick together and interfere with blood circulation. The result of these problems is severe shortage of oxygen followed by damage to vital organs and, in many cases, death. This potentially lethal genetic disorder is called sickle-cell anaemia.

The T in the DNA strand is replaced with base A to change the glutamic acid to valine.

People who are heterozygous for the mutant allele do not suffer sickle-cell anaemia. Instead they are found to have a milder condition called sickle-cell trait. Their red blood cells contain both forms of haemoglobin but do not show ‘sickling’. The slight anaemia that they tend to suffer does not prevent moderate activity.

The sickle-cell mutant allele is rare in most populations. However, in some parts of Africa up to 40% of the population have the heterozygous genotype. This is because sickle-cell trait sufferers are resistant to malaria. The parasite cannot make use of the red blood cells containing haemoglobin S. This situation, where a genetic disorder confers an advantage on its sufferers, is very unusual.

Phenylketonuria (PKU) Phenylalanine and tyrosine are two amino acids that human beings obtain from protein in their diet. During normal metabolism, excess phenylalanine is acted on by an enzyme.

Phenylketonuria is a genetic disorder cause by a mutation to a gene on chromosome 12 that normally codes for enzyme 1 in the pathway. Most commonly, the mutated gene has undergone a substitution of a nucleotide and missense occurs. The altered form of the protein expressed contains a copy of tryptophan in place of arginine and is non-functional. As a result of this inborn error of metabolism, phenylalanine is no longer converted to tyrosine. Instead it accumulates and some of it is converted to toxins. These poisonous metabolites inhibit one or more of the enzymes that control biochemical pathways in brain cells. The brain fails to develop properly, resulting in the person having severe learning difficulties. In Britain, new born babies are screened for PKU (blood sample) and sufferers are put on a diet containing minimum phenylalanine. By this means, the worst effects of PKU are reduced to a minimum. Sufferers are not albino as they can still obtain tyrosine in their diet to convert to melanin.

Beta (β) thalassemia A molecule of haemoglobin is composed of two alpha globin and two beta globin polypeptide chains. These polypeptides are encoded by genes. Beta (β) thalassemia is a genetic disorder caused by any one of several types of mutation that affect a gene on chromosome 11 that codes for beta-globin. One of the most common of these mutations is a substitution that occurs at a splice site on an intron and causes base G to be replaced by base A. There are several forms of β-thalassemia some more severe than others. One type, for example, is characterised by the complete lack of production of betaglobin; another by the production of an altered version of the protein. In either case, the sufferer has a relative excess of alpha-globin in their bloodstream, which tends to bind to, and damage, red blood cells. Patients with severe βthalassemia require medical treatment such as blood transfusions.

Duchenne muscular dystrophy (DMD) Duchenne muscular dystrophy (DMD) is caused by any one of several types of mutation to a particular gene on chromosome X, such as deletion or a nonsense mutation (more so the latter). The affected gene fails to code for a protein called dystrophin, which is essential for the normal functioning of muscles. In skeletal and cardiac muscle, for example, dystorphin is part of a group of proteins that strengthen muscle fibres and protect them from injury during contraction and relaxation. Duchenne muscular dystrophy is the most common form of muscular dystrophy (muscle wasting disease). In the absence of dystrophin, skeletal muscles become weak and lose their normal structure. This condition is accompanied by progressive loss of coordination. Sufferers are severely disabled from an early age and normally die young without passing the mutant allele on to the next generation. DMD is sex-linked and is almost entirely restricted to males, being passed on by carrier mothers to their sons.

Tay-Sachs disease Tay-Sachs disease is a genetic disorder resulting from a mutation to a gene on chromosome 15. Under normal circumstances the gene is responsible for encoding an enzyme that controls an essential biochemical reaction in nerve cells. Changes to the gene take the form of point mutations such as insertions and deletions, which result in the frameshift effect. The protein expressed is so different from the normal one that it is nonfunctional. As

a result,

the

enzyme’s

unprocessed

substrate

accumulates in brain cells. This leads to neurological degeneration, generalised paralysis and death at about 4 years of age.

Cystic Fibrosis Cystic fibrosis is a genetic disorder caused by a three base-pair deletion to a gene on chromosome 7. This type of mutation removes a codon for phenylalanine and causes the coded message to be seriously altered by the frameshift effect and produce a non-functional protein. The normal allele for the gene codes for a membrane protein that assists in the transport of chloride ions into and out of cells. In the absence of this protein an abnormally high concentration of chloride gathers outside cells. Those regions of the body that coat their cells with mucus become affected because the high concentration of chloride causes mucus to become thicker and stickier. Organs such as the lungs, pancreas and alimentary canal become congested and blocked. Regular pounding on the chest to clear thick mucus and daily use of antibiotics can extend a sufferer’s life into their thirties and beyond. Untreated, the sufferer normally dies at age 4-5 years.

Huntington’s Disease Huntington’s disease is caused by a gene on chromosome 4 that has been affected by a nucleotide sequence repeat expansion. This type of mutation results in the codon CAG being repeated more than 35 times. The affected gene no longer encodes a certain protein essential for the normal functioning of the nervous system. Instead it codes for a defective form of the protein bearing a long chain composed of repeats of glutamine (the amino acid encoded by CAG). Lack of the correct protein leads to:  Premature death of neurons in regions of the brain  Decreased production of neurotransmitters  Progressive degeneration of the central nervous system. Unlike all of the other genetic disorders described, the mutant allele for Huntington’s disease is dominant and therefore affects people with a heterozygous genotype. In addition, the symptoms of this genetic disorder often do not appear until the person reaches early middle age. Death usually follows 10-20 years later. Prior to the onset of the disease, each potential sufferer runs a 50% chance of passing the lethal allele on to each of their offspring before they themselves know if they are affected or not. The condition is incurable.

Fragile X syndrome Fragile x syndrome is a leading cause of a wide spectrum of inherited mental disabilities. It is characterised by a variety of physical features and mental limitations, such as a very elongated face, low muscle tone, nervous speech, poor memory and a very short attention span. This genetic disorder is caused by a nucleotide sequence repeat expansion of CGG coded from a region of the X chromosome. This mutation results in the failure of a gene to encode a protein that is normally active in brain synapses and involved in the control of synaptic plasticity. Lack of this essential protein results in retarded neural development. Whereas

the

gene

of

an

unaffected individual contains 6-53

repeats

of

the

CGG

triplet, a sufferer of fragile X syndrome may have as many as 4000 repeats. Such expansion of

the

tri-nucleotide

repeat

brings about silencing of the affected gene. There is no treatment condition.

available

for

this