Gene Therapy
The aim of gene therapy is to insert the normal, cloned DNA for a gene into the somatic cells of a patient who is defective in that gene as a result of some disease-causing mutation. The inserted DNA must be permanently integrated into the patient's chromosomes in such a way as to be properly transcribed and translated into the correct protein.For example, patients with severe combined immunodeficiency disease (SCID) have an immune deficiency as a result of mutations in either the adenosine deaminase (ADA) gene or a gene coding for an interleukin receptor subunit (X-linked severe combined immunodeficiency, or SCID-X1). Patients with both kinds of SCID have been successfully treated by incorporating functional copies of the appropriate gene into their cells [Gene Replacement Therapy].
Although gene therapy is an attractive therapeutic strategy for individuals with inherited diseases, the method is not without risks. For example, retrovirus-mediated gene transfer was able to correct SCID-X1 in 90% of patients. However, severe side effects may develop e.g. leukemias developed in several patients, due to activation of a hematopoietic oncogene. It is clear that gene therapy is still in its initial success right now!!
Transgenic Animals These animals can be produced by injecting a cloned gene into a fertilized egg. When the gene becomes successfully incorporated into a chromosome, it will be present in the germline of the resulting animal, and can be passed along from generation to generation.
An example is a giant mouse called “Supermouse” is produced by injecting the gene for rat growth hormone into a fertilized mouse egg. Sometimes, cloned mutant genes are used instead of normal genes! Such transgenic animals can then be used for the study of a corresponding human diseases. For example, transgenic mice carrying mutant copies of the dystrophin gene serve as animal models for the study of muscular dystrophy.
Miscellaneous subjects
Hexose Monophosphate Pathway (The Pentose Phosphate Pathway) The pentose phosphate pathway is an alternative route for the metabolism of glucose. It does not generate ATP but has two major functions: (1) The formation of NADPH for synthesis of fatty acids and steroids and (2) the synthesis of ribose phosphate for nucleotide and nucleic acid formation.The enzymes of the pentose phosphate pathway, as of glycolysis, are cytosolic. The sequence of reactions of the pathway may be divided into two phases: An oxidative nonreversible phase A nonoxidative reversible phase. In the first phase, glucose 6-phosphate undergoes dehydrogenation and decarboxylation to yield a pentose, ribulose 5-phosphate. In the second phase, ribulose 5-phosphate is converted back to glucose 6-phosphate by a series of reactions involving mainly two enzymes: transketolase and transaldolase.
Ribulose 5-phosphate is the substrate for two enzymes. Ribulose 5-phosphate 3-epimerase alters the configuration about carbon 3, forming another ketopentose, xylulose 5-phosphate. Ribose 5-phosphate ketoisomerase converts ribulose 5-phosphate to the corresponding aldopentose, ribose 5-phosphate, which is the precursor of the ribose required for nucleotide and nucleic acid synthesis.
Xanthinurea
Xanthinuria, is a rare genetic disorder causing the accumulation of xanthine. It is caused by a deficiency of the enzyme xanthine oxidase which is an enzyme necessary for converting xanthine to uric acid. It was first formally characterized in 1954.Sufferers have unusually high concentrations of xanthine in their blood and urine, which can lead to health problems such as renal failure and xanthine kidney stones, one of the rarest types of kidney stones. There is no specific treatment beyond maintaining a high fluid intake and avoiding foods that are high in purine.
Thalassemia
The fundamental abnormality in thalassemia is impaired production of either the alpha or beta hemoglobin chain. Thalassemia is a difficult subject to explain, since the condition is not a single disorder, but a group of defects with similar clinical effects.The loss of one gene diminishes the production of the alpha protein only slightly. This condition is so close to normal that it can be detected only by specialized laboratory techniques that, until recently, were confined to research laboratories. A person with this condition is called a "silent carrier" because of the difficulty in detection.
The loss of two genes (two-gene deletion alpha thalassemia) produces a condition with small red blood cells, and at most a mild anemia. People with this condition look and feel normal. The condition can be detected by routine blood testing. The loss of three alpha genes produces a serious hematological problem (three-gene deletion alpha thalassemia). Patients with this condition have a severe anemia, and often require blood transfusions to survive. The severe imbalance between the alpha chain production (now powered by one gene, instead of four) and beta chain production (which is normal) causes an accumulation of beta chains inside the red blood cells.
Normally, beta chains pair only with alpha chains. With three-gene deletion alpha thalassemia, however, beta chains begin to associate in groups of four, producing an abnormal hemoglobin, called "hemoglobin H". The condition is called "hemoglobin H disease". Hemoglobin H has two problems: 1. It does not carry oxygen properly, making it functionally useless to the cell. 2. Hemoglobin H protein damages the membrane that surrounds the red cell, accelerating cell destruction. The combination of the very low production of alpha chains and destruction of red cells in hemoglobin H disease produces a severe, life-threatening anemia. Untreated, most patients die in childhood or early adolescence.
The loss of all four alpha genes produces a condition that is incompatible with life. The gamma chains produced during fetal life associate in groups of four to form an abnormal hemoglobin called "hemoglobin Barts". Most people with four-gene deletion alpha thalassemia die in utero or shortly after birth. Rarely, four gene deletion alpha thalassemia has been detected in utero. In utero; blood transfusions have saved some of these children. These patients require life-long transfusions and other medical support.
BetaThalassemia The fact that there are only two genes for the beta chain of hemoglobin makes beta thalassemia a bit simpler to understand than alpha thalassemia. Unlike alpha thalassemia, beta thalassemia rarely arises from the complete loss of a beta globin gene. The beta globin gene is present, but produces little beta globin protein. The degree of suppression varies.
Many causes of suppressed beta globin gene expression have been found. In some cases, the affected gene makes essentially no beta globin protein (beta-0-thalassemia). In other cases, the production of beta chain protein is lower than normal, but not zero (beta-(+)-thalassemia). The severity of beta thalassemia depends in part on the type of beta thalassemic genes that a person has inherited.
i) one-gene beta thalassemia has one beta globin gene that is normal, and a second, affected gene with a variably reduced production of beta globin. The degree of imbalance with the alpha globin depends on the residual production capacity of the defective beta globin gene. Even when the affected gene produces no beta chain, the condition is mild since one beta gene functions normally. The red cells are small and a mild anemia may exist. People with this condition generally have no symptoms. The condition can be detected by a routine laboratory blood evaluation.
Note: the one-gene beta thalassemia and the two-gene alpha thalassemia are very similar, from a clinical point of view. Each results in small red cells and a mild anemia.
(ii) two-gene beta thalassemia produces a severe anemia and a potentially life-threatening condition. The severity of the disorder depends in part on the combination of genes that have been inherited: beta-0-thal/ beta-0-thal; beta-0-thal/ beta-(+)-thal; beta-(+)-thal/ beta-(+)-thal. The beta-(+)-thalassemia genes vary greatly in their ability to produce normal hemoglobin. Consequently, the clinical picture is more complex than might otherwise be the case for three genetic possibilities outlined.
Relationship of the Genetic and Clinical Classifications of Thalassemia: The advent of modern molecular biology permits the genetic classification of thalassemias. A rough correlation exists between the clinical and genetic classifications. The relationship between genetics and clinical state is not absolute, however: * thalassemia trait (minor)- normal beta gene/ thalassemia gene ( beta zero or +) * thalassemia intermedia- often two beta-(+)-genes * thalassemia major- two beta-(+)-genes (where the plus is not substantial); beta-(+)-gene/ beta-0-gene; beta-0-gene/ beta-0-gene