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Single Gene Defect Genetic Diseases
The presence of a mutant gene, chromosomal aberration and the complexity of the relationship of group of genes with the environmental factors (mutagens) are all well exhibited by various common and rare kind of diseases. The diseases developed as a result of mutation are classified under genetic diseases. A defective single gene (mutant) is powerful enough to develop a disease which may be even fatal to the affected person. The genetic disease is either inherent or found to develop in the offspring alone as a result of mutant gene present in the sex chromosomes.

Inheritance is the passing of disease from one generation to the next which usually occurs in three ways. They are Autosomal dominant inheritance, Autosomal recessive inheritance and X-linked inheritance.

Autosomal dominant inheritance: The presence of mutated allele in either one of the parents causes disease in the offspring. For example, combination of a male parent with one mutant allele (dD) with a normal female parent (DD) produces two mutated offspring (dD) and two normal offspring (DD). The individual with one normal allele (D) and one mutated allele (d) is called as a heterozygous individual (dD).

Autosomal recessive inheritance: The disease is developed in the offspring by the inheritance of mutant alleles one each from both the parents. For example, combination of a carrier male parent (Dd) with a carrier female parent (Dd) results in two carriers (Dd), a normal offspring (DD) and an affected offspring (dd) also called as homozygous individual.

X-linked inheritance: The presence of mutant allele in X – chromosome causes X-linked inheritance. The male population is the affected group because of the presence of only one X chromosome (XY) whereas the female with two X chromosomes (XX) may usually be carriers.

The point mutation and the gross mutation are to be blamed for the defective single gene disorders. Missense/silent mutations, nonsense mutation, frameshift mutation, splice site mutation and promoter mutation falls under one roof called point mutation. The insertion and deletion mutation, gene rearrangement and trinucleotide repeat mutation are classified as gross mutation. Some of the single gene mutation diseases are Hemophilia A and B, Thalassemia, sickle cell anemia, Duchenne muscular dystrophy, Becker muscular dystrophy, Fragile X syndrome, Huntington’s disease, Neurofibromatosis, Phenylketonuria and cystic fibrosis.

Hemophilia A: A condition of excess bleeding developed due to the mutation of Factor VIII gene and the mutation type is either frame shift or insertion or deletion mutation and it is a X-linked inherited disease.

Hemophilia B: Excess unusual bleeding due to the mutation of the promoter gene responsible for protein Factor IX which stimulates clotting of blood. Mutation of the gene arrests the blood clotting property of Factor IX causing unusual bleeding in the affected person and it is an X-linked inherited disorder.

Thalassemia: The anemic condition due to either splice site mutation or nonsense mutation of the gene responsible for β-globin resulting in the termination of β globin synthesis causes β Thalassemia. This is Autosomal recessive inherited disorder.

Sickle cell Anemia: The Autosomal recessive inherited disease occurs as a result of misense mutation to the gene coding β globin. Sickle cell anemia is represented by the presence of short lived sickle shaped red blood cell causing anemia and ischemia.

Huntington’s disease: The repetition of trinucleotide sequence causing mutation in the gene sequence coding for huntingtin causes Huntington disease, a Autosomal dominant inherited disorder. The disease is characterized by dementia.

Cystic Fibrosis: The Autosomal recessive disorder associated with lung damage symptoms due to the deletion mutation of the CFTR gene.

Neurofibromatosis: Autosomal dominant disorder due to the mutation of the NF-1(Type 1 disease) and NF-2 (type 2 disease) gene causing tumor of the nerve tissues.

If we see the Autosomal recessive type disorder, both the parents acts as carriers and the product receiving both the mutant allele (one from the father and the other from the mother) becomes subject for the genetic disease. The parents may be informed about the possibility of genetic disease in their child in advance if both the parents are identified as carriers. Gene Tracking is the technique employed to detect the carriers in a family. This involves the detection of restriction fragment length polymorphisms in a genomic DNA sample by southern blotting technique and also by using DNA repeat sequences like minisatellite DNA and microsatellite DNA.
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Single gene disorders and selective pressure

Single gene disorders represent a large group of inherited disorders. So far, over 10 000 genetic disorders are identified as a result of a single gene defect. Despite being familiar with mechanism of inheritance (autosomal, X-linked, dominant, recessive…), single gene disorders can’t be prevented unless genetic testing is performed before or during pregnancy. Pathology behind most diseases is well known, but it still remains unknown why nature tolerate “errors” in genetic material that are very harmful for the carriers/diseased? Answer to that question may be associated with sickle cell anemia, a well known single gene disorder, and ability of their carriers to tolerate malaria. Molecular mechanism behind this protective effect has been clarified recently.

Single cell anemia will develop as a consequence of point mutation in the beta hemoglobin gene located on the chromosome 11. Instead of glutamine, amino-acid valine will be inserted and altered beta chains will be formed. Mutated beta chains and unchanged alpha chains will form hemoglobin S. This type of hemoglobin will aggregate when person become exposed to low oxygen level, which will lead to formation of sickle shaped red blood cell. Sickle erythrocytes have decreased elasticity, which is required for optimal function of the red blood cells and their wriggling through narrow blood vessels, such as capillaries. Without elasticity and ability to return to the normal shape, sickle red blood cells will occlude smallest blood vessels and induce ischemia. Besides inability to perform normal function in the body, these type of red blood cells have very short lifespan and bone marrow can’t compensate their loss easily, especially because hemoglobin A (made of alpha and beta chains) represent the majority of hemoglobin types in the body (96-97%). People diagnosed with sickle cell anemia live between 42-48 years, but with proper therapy, life can be prolonged beyond 50 years.

Sickle cell anemia is most commonly recorded in tropic and sub-tropic areas of sub-Saharan areas (three quarters of all world cases). In the mid of the last century, scientists focused on sickle cell anemia discovered that carriers of mutated allele can survive malaria and that selective pressure increases the number of people carrying mutation in areas endemic for malaria. Today 10-40% of people in Africa carry mutation for hemoglobin S. Sickle cell anemia is example of genetic disorder that has heterozygous advantage: although 25% of the offspring has a chance to develop disease in case that both parent have impaired allele, carriers of the mutation will not develop classical diseased phenotype and they will be resistant to malaria.

Malaria is transmitted by mosquitoes that carry blood parasite Plasmodium falciparum. This protozoan species inhabit liver and red blood cells where it divides and increase its number. Classical symptoms of malaria (chills and fever) are associated with rupture of infected erythrocytes. Cerebral malaria is a dangerous complication of the malaria disease that usually affects children and may induce irreversible consequences in the neuronal functioning even after malaria is cured. It can end fatally. People who have sickle cell anemia are resistant to malaria, while those that carry just a single allele develop less severe symptoms of disease when they become infected. Scientific community was eager to discover mechanism that provides resistance against malaria, because without mechanism - proper medication can't be developed. Many believed that sickle shape of the erythrocytes prevents Plasmodium from entering the cell, but latest experiments discovered another factor that might contribute to the resistance against malaria. When researchers infected mouse with mutation in hemoglobin gene with Plasmodium, they noted that mouse doesn’t develop cerebral malaria (just like people with one impaired allele). Number of available normally shaped erythrocytes prevents Plasmodium to increase its number which reduces severity of infection immediately. Previous studies showed that carbon monoxide provides protection against cerebral malaria and in experiment with mice, researchers discovered that sickle cells produce increased amount of heme oxygenase-1, an enzyme responsible for carbon monoxide production. Increased level of carbon monoxide doesn’t interrupt Plasmodium’s cycle, but prevents brain damage typical for people with normal erythrocytes. Exact mechanism of carbon monoxide protection remains to be discovered, but it can be concluded that persons with hemoglobin S mutation develop lesser symptoms of disease due to lower number of parasites and their inability to induce cerebral damage (prevented by increased carbon monoxide production via enzymatic activity of sickle cells).

Mutations happen all the time and they shape evolution of all living creatures on the Earth: bad mutation will be eliminated, beneficial will remain in the population. Sometimes, mutation has two faces, good and bad. In that case, nature will select where and when mutation will spread. Just like with sickle cell anemia.
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