Cystic Fibrosis

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Cystic Fibrosis

Cystic fibrosis (CF) is one of the most common genetic diseases and one of the best known to the general public. There are approximately one thousand new cases of CF in the United States every year, and approximately thirty thousand people in the country are currently affected. In many ways, it has come to be viewed, along with sickle-cell disease, as a prototypical recessive genetic disorder, one that can teach us a great deal about the molecular basis of disease, population genetics, and delivery of genetic screening services.

Clinical Features

CF is a multisystem disease, affecting a number of different organs and tissues throughout the body. Most of these manifestations have in common the production of abnormally viscous secretions from glands and surface epithelial cells . In the lung the mucus secretions from the bronchial epithelial cells are unusually thick. They are difficult to clear properly from the airway passages and, instead, tend to collect and obstruct the bronchial tree, while providing a perfect culture medium for dangerous bacteria. Over time, repeated bacterial infections damage and destroy the lung tissue, leading to chronic breathing problems and, eventually, to the loss of viable lung function. Indeed, the pulmonary manifestations of the disease are the main cause of death in most CF patients.

Obstruction in other organs is also seen. In the pancreas it leads to an insufficiency of pancreatic enzymes and malabsorption during digestion; in the nose and sinuses, it produces chronic sinusitis; and in the intestines, in a small minority of newborn infants with CF, it produces an often fatal condition called meconium ileus. Altered secretions also occur in the sweat glands, so that the sweat of CF patients has an abnormally high salt content. In fact, in the early days of medicine, the diagnosis of CF was often made by licking the skin and tasting the sweat! One additional mysterious clinical feature of CF occurs only in men with the disorder: They are infertile due to blockage or congenital absence of the vas deferens, the tube through which sperm pass prior to ejaculation.

Laboratory Diagnosis

Since the clinical symptoms of CF are so varied, diagnosis is aided by laboratory tests. For many years the only definitive test available was sweat chloride analysis, which detects and quantifies the abnormally high salt concentrations in the sweat of CF patients. Since the causative gene was discovered in 1989, as described below, patients can now also be diagnosed by DNA testing, which detects mutations in the gene.

Mode of Inheritance

CF is a classical autosomal recessive disease, in which affected patients are born to parents who are both carriersthat is, they have a mutation in one of their two CF genes. Carrier couples have a one-in-four risk of producing an affected child with each pregnancy. The carriers themselves are completely asymptomatic and even have normal sweat chloride tests.


There is still no cure for this disease, but supportive therapies have improved markedly in the last twenty years. The recurrent lung infections are now much better controlled with powerful, new-generation antibiotics, though, unfortunately, many patients eventually develop infections with drug-resistant bacteria. A variety of approaches are used to break up and remove the thick mucus secretions in the lung, including mucolytic (mucusbreaking) agents, bronchodilators, and chest physical therapy. One type of mucolytic treatment is DNase, a DNA-destroying enzyme that breaks up the long, sticky DNA strands left by dying cells. Some patients with end-stage lung disease can be rescued by lung transplantation. Patients with pancreatic obstruction can be managed with pancreatic enzyme supplements, and affected men with vas deferens obstruction have been able to father children by a technique called sperm aspiration, followed by in vitro fertilization.

The ultimate hope for the cure of CF lies in gene replacement therapy. A number of clinical trials are under way, most attempting to deliver the normal CF gene to the bronchial epithelium by aerosol spray, using a viral vector (usually adenovirus, a common respiratory virus that naturally targets the desired tissue). Thus far the attempts have not been completely successful, as most patients develop an immune response against the virus during the course of therapy. But with the median life expectancy of CF patients now at thirty years just through conventional therapies, the hope is that many CF patients alive today will survive long enough to avail themselves of gene therapy once it is perfected.

The Cystic Fibrosis Gene and CFTR Protein

The identification of the causative gene for CF in 1989 represented one of the great triumphs of molecular genetic research up to that time. With the gene's identification having preceded the official start of the Human Genome Project by one year, the search for the CF gene proceeded without the benefits of the fully mapped genome that we have today. Hence, some of the techniques used to identify the CF gene, such as "gene walking" and "gene jumping," are no longer used extensively.

The CF gene was identified through linkage analysis and positional cloning . Whereas nowadays the map of the human genome is saturated with these markers, which serve as convenient "signposts" in gene mapping studies, this was not the case when the CF mapping was done, and more laborious, brute-force techniques such as those mentioned above had to be employed. Thus, it was dramatic news indeed when the causative gene was found on chromosome 7.

As might have been expected based on the secretory defects in the disease, the gene, dubbed "cystic fibrosis transmembrane conductance regulator" (CFTR ), encodes an ion-channel protein in epithelial cell membranes. The gene is quite large250,000 nucleotidesand the spectrum of mutations in CF patients continues to grow. At the time of this writing, more than 950 different mutations have been reported. Most of these are quite rare and may only be found in individual families. A few are more common, most notably a three-nucleotide deletion of codon 508, called ΔF508, which is found in approximately 70 percent of Caucasian CF carriers. Several others are present in 1 percent to 3 percent of carriers, while the remainder are very rare, except for some that are found at higher frequency in particular ethnic and racial groups (such as W1282X in the Ashkenazi-Jewish population and 3120+1GA in the African-American population).

The ΔF508 mutation in the CFTR gene deletes a phenylalanine amino acid from the final protein. Like other membrane proteins, CFTR is made at the endoplasmic reticulum in the interior of the cell, and must be transported to the plasma membrane to function. The absence of this amino acid results in improper folding of the CFTR protein within the endoplasmic reticulum, which causes it to be degraded by the cell's protein-recycling machinery before it reaches the membrane. Some of the less common mutations prevent any protein synthesis by introducing a stop codon into the gene, while others allow the protein to reach the membrane but without functioning properly.

The CFTR protein forms a pore to allow chloride ions to pass through the plasma membrane. The full range of functions served by this pore is not known, but the sticky secretions of CF are believed to result when chloride ions in the salty fluid secreted by the epithelial cells cannot be recovered by the membrane protein.

Cystic Fibrosis DNA Testing and Screening

The discovery of the CFTR gene raised hopes that the detection of mutations at the DNA level could supplement the traditional sweat test for CF diagnosis and, more importantly, might be used to identify carriers in the general population so that they could be offered genetic counseling. Unfortunately, these goals have been hampered by the large number of possible mutations in the gene, since present-day DNA tests can detect only a small subset of them. As in most recessive diseases, the vast majority of carriers have no family history of the disorder and do not discover that they are carriers until they happen to have a child with another carrier, giving birth to their first affected child.

CF is an appealing target for population carrier screening simply because of the relatively high carrier frequency in the general population. One in twenty-nine Caucasians, one in forty-six Hispanics, one in sixty-five African Americans, and one in ninety Asian Americans are carriers. It is not known why the mutation frequency is so high, especially in European populations. Some have proposed, using the analogy of the sickle-cell gene conferring relative resistance to malaria, that the mutations must have a protective effect against some disease appearing in European history, such as cholera or tuberculosis.

But all of this is just speculation. DNA screening of the entire adult population could potentially identify those couples at risk, who could then be offered prenatal diagnosis, affording couples the opportunity to consider their options. After several pilot studies and much debate at the national level, it has now been recommended that screening for the twenty-five most frequent CFTR mutations be offered to all couples expecting a child or planning a pregnancy. So most of the students reading this book will eventually be offered this DNA test!

see also Cell, Eukaryotic; Gene Discovery; Gene Therapy; Genetic Counseling; Heterozygote Advantage; Human Disease Genes, Identification of; Inheritance Patterns; Population Screening; Proteins.

Wayne W. Grody


Welsh, Michael J., and Alan E. Smith. "Cystic Fibrosis." Scientific American 273 (1995): 53-59.

Internet Resources

"Airway Clearance Techniques." University of Wisconsin Medical School. <>.

Cystic Fibrosis Foundation. <>.

Grody, Wayne W., et al. "Laboratory Standards and Guidelines for Population-Based Cystic Fibrosis Carrier Screening." Genetics in Medicine 3 (2001): 149-154. <>.


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A medical term that refers to the excessive growth of fibrous tissue in some part of the body. Many types of fibroses are known, including a number that affect the respiratory system. A number of these respiratory fibroses, including such conditions as black lung disease , silicosis, asbestosis , berylliosis, and byssinosis, are caused by environmental factors. A fibrosis develops when a person inhales very tiny solid particles or liquid droplets over many years or decades. Part of the body's reaction to these foreign particles is to enmesh them in fibrous tissue. The disease name usually suggests the agent that causes the disease. Silicosis, for example, is caused by the inhalation of silica, tiny sand-like particles. Occupational sources of silicosis include rock mining, quarrying, stone cutting, and sandblasting. Berylliosis is caused by the inhalation of beryllium particles over a period of time, and byssinosis (from byssos, the Greek word for flax)is found among textile workers who inhale flax, cotton or hemp fibers.


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fi·bro·sis / fīˈbrōsəs/ • n. Med. the thickening and scarring of connective tissue, usually as a result of injury.DERIVATIVES: fi·brot·ic / fīˈbrätik/ adj.


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fibrosis (fy-broh-sis) n. thickening and scarring of connective tissue, most often a consequence of inflammation or injury. pulmonary interstitial f. thickening and stiffening of the lining of the alveoli causing progressive breathlessness. See also cystic fibrosis, retroperitoneal fibrosis.
fibrotic adj.