Genetic Disorders - Cystic Fibrosis

Cystic fibrosis (CF) is the most common inherited fatal disease of children and young adults in the United States. It occurs in about one in every 3,000 Caucasian births, one in 15,000 African-Americans and one in 31,000 Asian-Americans. According to the NIH (http://www.genome.gov/10001213), approximately 30,000 young people had the disease in 2005; their median (half above and half below) life span is thirty years. An estimated twelve million Americans (one in twenty-five), almost all of whom are white, are symptomless carriers of the CF gene. Like sickle-cell disease, it is a recessive genetic disorder—in order to inherit this disease, a child must receive the CF gene from both parents.

In 1989 the CF gene was identified, and in 1991 it was cloned and sequenced. It is located on the long arm FIGURE 5.12
Location of the CFTR gene
SOURCE: "Where is the CFTR gene located?" in Genetics Home Reference, U.S. National Library of Medicine, 2004, http://ghr.nlm.nih.gov/genecftr (accessed February 8, 2005) of chromosome 7 at position 31.2 (See Figure 5.12.) The gene was called cystic fibrosis transmembrane conductance regulator (CFTR) because it was discovered to encode a membrane protein that controls the transit of chloride ions across the plasma membrane of cells. Nearly 1,000 mutations of the large gene—250,000 nucleotides—have been identified. Though most are FIGURE 5.13
Defects that cause cystic fibrosis
SOURCE: "Defects in CFTR Production That Can Cause Cystic Fibrosis," in Genetics, vol. 1, A–D, Macmillan Reference USA, Gale Group, 2002 extremely rare, several account for more than two-thirds of all mutations. Figure 5.13 shows three types of defects in cystic fibrosis transmembrane conductance regulator that can cause CF. The most frequently occurring mutation causes faulty processing of the protein such that the protein is degraded before it reaches the cell membrane.

The mutated versions of the gene found in people with CF were seen to cause relatively modest impairment of chloride transport in cells. But this seemingly minor defect can result in a multisystem disease that affects organs and tissues throughout the body, provoking abnormal, thick secretions from glands and epithelial cells. Ultimately, these secretions fill the lungs and cause affected children to die of respiratory failure.

The progression from the defective gene and protein it encodes to life-threatening illness follows this complex path:

1. The defect in chloride passage across the cell membrane indirectly produces an accumulation of thick mucus secretions in the lungs.
2. The bacteria Pseudomonas aeruginosa grows in the mucus.
3. In a campaign to combat the bacterial invasion, the body's immune system is activated but is unable to access the bacteria because the thick mucus protects it.
4. The immune reaction persists and becomes chronic, resulting in inflammation that harms the lung.
5. Ultimately, it is the affected individual's own immune response, rather than the defective CF gene, protein, or the bacterial infection, that produces the often fatal damage to the lungs.

At first, a child with CF does not appear to be suffering from a serious illness, but the diagnosis is usually made by the age of three. Often, the only signs are a persistent cough, a large appetite but poor weight gain, an extremely salty taste to the skin, and large, foul-smelling bowel movements. A simple "sweat test" is currently the standard diagnostic test for CF. The test measures the amount of salt in the sweat; abnormally high levels are the hallmark of cystic fibrosis. Over time children with CF develop great difficulty in breathing. The CF gene causes the body to produce thick, sticky mucus in the lungs and pancreas, causing difficulty in breathing and interference with digestion.

CF Gene-Screening Falters

In August 1989 researchers isolated the specific gene that causes CF. The mutation of this gene accounts for about 70% of the cases of the disease. In 1990 scientists successfully corrected the biochemical defect by inserting a healthy gene into diseased cells grown in the laboratory, a major step toward developing new therapies for the disease. In 1992 they injected healthy genes into laboratory rats by using a deactivated common cold virus as the delivery agent. The rats began to manufacture the missing protein, which regulates the chloride and sodium in the tissues, preventing the deadly buildup of mucus. Scientists were hopeful that within a few years CF would be eliminated as a fatal disease, giving many children the chance for healthy, normal lives.

In 1993, however, optimism faded when the medical community discovered that the CF gene was more complicated than expected. Scientists found that the gene can be mutated at more than 950 points, and more points are appearing at an alarming rate. At the same time, they discovered that many people who have inherited mutated genes from both parents do not have cystic fibrosis. With so many possible mutations, the potential combinations in a person who inherits one gene from each parent are immeasurable.

The combinations of different mutations create different effects. Some may result in crippling and fatal CF, while others may cause less serious disorders, such as infertility, asthma, or chronic bronchitis. To further complicate the picture, other genes can alter the way different mutations of the CF gene affect the body.

In 2005 the Cystic Fibrosis Foundation continued to support clinical research studies in human gene therapy. Several studies used the adenovirus rather than the common cold virus as the vehicle for delivering healthy genes to lung or nasal tissue. Another study is using liposomes (fat cells) as a delivery vehicle. Still another form of gene therapy uses a compacted DNA technology. The nonviral gene transfer system compacts single copies of the healthy CFTR gene so that they are small enough to pass through a cell membrane into the nucleus. The goal is for the DNA to produce the CFTR protein that is needed to correct the basic defect in CF cells.

Researchers are also finding that CF mutations may be much more common than previously thought. For example, 5,000 healthy women receiving prenatal care at Kaiser Permanente in northern California were tested for the CF gene, thought to be present in less than 1% of the population. Of those screened, 11% had the mutation. This finding may indicate that many more common diseases, such as asthma, may be caused by mutations of the CF gene. Other scientists have speculated that the frequency of CF carriers among people of European descent may have, at some point in time, conferred immunity to some other disorder, in much the same way that the sickle-cell carriers were protected from malaria.

CF Carriers Do Not Always Inform Family Members

Since there is a relatively high frequency of carriers of the defective gene in the general population, in 2000 the NIH, the American College of Medical Genetics, and the American College of Obstetricians and Gynecologists issued a recommendation that CF screening be offered to every white woman who is pregnant or considering having a baby. However, the same year the results of a research study conducted at Northwestern University Medical School in Chicago found that many people who carry the CF gene fail to inform family members about their risk.

The investigators and other health educators believe that if carriers were better informed about their risks they might be more likely to disclose them. Pretest education and counseling were seen as key to increasing carriers' understanding of the significance of findings and their family planning options. For example, when both parents are carriers, the risk of their child having CF is one in four, and the risk of their child being a carrier is one in two. In this case parents may choose to have prenatal diagnosis using chorionic villus sampling (CVS) or amniocentesis to find out whether their unborn child will have the disease. Alternatively, they may choose to use assisted reproductive technology such as in vitro fertilization (in which the egg and sperm are united outside of the body) because it offers the option of preimplantation diagnosis. This is a genetic test that enables parents undergoing in vitro fertilization to screen an embryo for CF genetic mutations before it is implanted in the uterus to grow and develop.