Other Free Encyclopedias » Medicine Encyclopedia » Genetics in Medicine - Part 3

Pleiotropy - Signaling Pathways

blood cell disease cells

Pleiotropy is the phenomenon whereby a single gene has multiple consequences in numerous tissues. Pleiotropic effects stem from both normal and mutated genes, but those caused by mutations are often more noticeable and easier to study. Pleiotropy is actually more common than its opposite, since in a complex organism, a protein from a single gene is likely to be expressed in more than one tissue, and the cascade of problems caused by a mutation is likely to lead to numerous complications throughout the organism. Single-gene defects with effects in only one tissue are more common for nonessential features such as hair texture or eye color.

Sickle cell disease is a classic example of pleiotropy. This disease develops in persons carrying two defective alleles for a blood protein, beta-hemoglobin. Mutant beta-hemoglobins are misaligned inside a blood cell and cause misshapen red blood cells at low oxygen concentrations. Deformed blood cells impair circulation. Impaired circulation damages kidneys and bone. In this case, the gene defect itself only affects one tissue, the blood. The consequences of that defect are found in other tissues and organs.

One baby in three thousand to four thousand births is born with neurofibromatosis, an autosomal dominant disease caused by mutation in a tumor suppressor gene that helps regulate cell division and cell-cell contacts. A truncated version of the tumor suppression protein, neurofibromin (NF I) is implicated in the disease. This mutant protein can come from mis-sense or nonsense mutations, or from reading-frame shifts after a repetitive element called Alu is inserted upstream of the NF I reading frame (a reading frame is the DNA that codes for proteins). Because the mutant protein is unable to regulate cell division, tumors grow on the nerves throughout the body. The tumors produce collateral damage: low blood sugar, intestinal bleeding, café-au-lait spots on the skin, mental retardation, heart problems, high blood pressure, fractures, spinal cord lesions, blindness, aneurysms, arthritis, and respiratory distress.

Many pleiotropic conditions arise from genes whose products are involved in signaling and regulation pathways. Because these proteins coordinate daily life in numerous tissues, defects in them have numerous consequences, as one breakdown leads to another.

Myotonic dystrophy is another autosomal dominant disorder. A gene for a protein—a kinase, involved in signalling and communication within the cell—is burdened with up to three thousand extra pieces of DNA. The extra DNA comes from trinucleotides (CTG)n that are added by mistake during DNA duplication, both in germ line cells and during early cell divisions The café-au-lait spots typical of neurofibromatosis are evident on this patient's hand. in the embryo. During transcription and translation, the kinase is not put together right, and the kinase's work in muscles goes badly. Muscles contract but cannot relax quickly. Young persons may have heart attacks, generalized muscle weakness, and loss of bulk. Swallowing and speech is hard, due to weak muscles in the tongue and neck. Other pleiotropic effects include baldness, cataracts, and changes in intelligence.

Pleiotropic outcomes are common with hormones. Hormones are signals that create multiple responses in tissues that carry receptors for them. The receptor binds to the hormone and triggers a cascade of reactions inside the cell. A defective receptor loses or misinterprets the signal. When the hormone insulin meets defective insulin receptors on an individual's cells, the person is more likely to develop type II diabetes. Cells do not open their gateways to let sugar in from the bloodstream, and the cells almost starve to death in the midst of plenty. Meanwhile, sugar accumulates in the blood and causes all sorts of ramifications for blood circulation, and it damages capillaries in all areas, from kidneys, to eyes, to feet. Gangrene, mental disturbances, kidney failure, and blindness can and do occur. Diminished give-and-take of sugar molecules across cell membranes leads to the multifaceted disease diabetes.

Susanne D. Dyby

Bibliography

Solomon, Eldra Pearl, and Linda R. Berg. The World of Biology, 5th ed. Philadelphia:Saunders College Publishing, 1995.

Internet Resources

National Center for Biotechnology Information. <www.ncbi.nlm.nih.gov>.

United States National Library of Medicine. <www.nlm.nih.gov>.

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