Navigate Exhibit by Clicking here Diagnosing and Treating Genetic Diseases
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When you know the genetic mutations that cause a disease, you may be able to intervene to lessen the diseaseís effects. And you may also be able to develop genetic tests for the mutations so that people can learn if they are more likely to develop a disease, or if they are carriers of the trait and may pass it on to their children. 

Searching for the genes involved in a genetic disease involves discovering which gene has been mutated and how it has been mutated. Because there may be more than one mutation in a gene which can cause a genetic disease, the search is often long. To intervene in the disease, you have to know what the gene is supposed to do, and what it isnít doing.

  Linkage diagram - Courtesy of the National Human Genome Research Institute

Courtesy of the National Human Genome Research Institute

One way researchers discover which genes go with what disease is through a technique called linkage analysis. By sampling DNA from families with many cases of a genetic disease, researchers can compare the DNA of affected family members to the DNA of family members who donít get the disease. Similar DNA segments in affected relatives mark specific chromosomes where scientists should search for the gene.

Here are the stories of four genetic diseases. Click on one to learn more.

Familial Hypercholesterolemia (one form of inherited high cholesterol)

Chronic Granulomatous Disease

Breast Cancer

Cystic Fibrosis

What is FH (familial hypercholesterolemia)?

Cells need cholesterol, a type of fat, to help them function and to build and maintain their cell walls. Cells get cholesterol delivered to them from low density lipoprotein (LDL) in the blood. Extra LDL (and the cholesterol it carries) normally is removed by receptors in the liver. A defect in the gene that creates LDL receptors in the liver causes FH. Not having enough receptors or having defective receptors means that the cholesterol is not removed from the body. Instead, the cholesterol builds fatty deposits in the arteries, blocking them and causing heart disease.
Graphic of LDL gene mutations - Courtesy of Dr. Joseph Goldstein, University of Texas Southwestern Medical School at Dallas
Courtesy of Dr. Joseph Goldstein, University of Texas Southwestern Medical School at Dallas.

Who is at risk?

About one person in 500 carries one FH allele and has an increased risk of heart disease. That means that nearly 500,000 Americans are have one defective allele. Most donít know it. About one person in a million has two FH alleles; these people often have heart attacks and die before age 20. Xanthomas (lumps of fatty tissue) are often a sign of this serious form of FH. People descended from French Canadians, South African whites, Finns, and Christian Lebanese often have the two FH alleles.

In 1973, Drs. Michael Brown and Joseph Goldstein and their colleagues at the University of Texas Southwestern Medical School at Dallas discovered the LDL receptors in the liver. Then they proved that a lack of LDL receptors causes a buildup of cholesterol. By purifying the LDL receptor protein, they isolated the gene responsible for FH in 1984. They received a Nobel Prize for describing how the gene, the protein, the receptors, and LDL work in the bodyís cholesterol system.

Patient with xanothomas - Courtesy of Dr. Joseph Goldstein, University of Texas Southwestern at Dallas
Patient with xanothomas. Courtesy of Dr. Joseph Goldstein, University of Texas Southwestern at Dallas.


Dr. Michael Brown and Dr. Joseph Goldstein and the Nobel Prize. Courtesy of Dr. Joseph Goldstein, University of Texas Southwestern Medical School at Dallas.


How is FH treated?

People who have only one FH allele can follow a low-fat, low-cholesterol diet, exercise, and take special drugs to reduce their risk of heart disease. People with two FH alleles may benefit from "apheresis" every two weeks, a process that removes LDL from their blood.

In the first FH gene therapy trial, researchers removed 10% of a womanís liver and grew cells from her liver in the laboratory. Then they altered a virus in the laboratory so that it contained the missing gene but could not reproduce itself.  They added the virus to the liver cells, and the virus inserted the missing gene into the cells.  Finally, the reinjected the "repaired" cells into her.  Her cholesterol level lowered moderately, but whether the therapy worked or the level decreased for some other reason is unclear. Five patients have been treated with mixed results. 



Low fat food and excercise. Courtesy of National Cancer Institute.


FH is a dominant trait.
Mutation sin LDL receptor gene

Heredity diagram

Slide of Dr. Wilson's experimental surgery - Courtesy of the National Human Genome Research Institute
Slide of Dr. Wilson's experiments. Courtesy of the National Human Genome Research Institute.

Chronic Granulomatous Disease (CGD)

The most common white blood cells -- neutrophils -- combat infections by producing germ-killing substances: hydrogen peroxide and bleach. People with CGD have genetic mutations that prevent the blood cells from making the proteins necessary for this process. As a result, infections that most of us easily fight are life-threatening to people with CGD.

Two-thirds of people with CGD are males who inherited the disease on the X-chromosome from their mother (males have an X-chromosome from their mother and a Y-chromosome from their father). In these cases, CGD is called an X-linked genetic disease. In general, females do not have problems when one of their X-chromosomes carries the X-linked CGD mutation. Non-X-linked forms of CGD affect both boys and girls.  
Hereditary Diagram

Heredity  diagram

From gene to protein

In 1985, Dr. Uta Francke at Yale University and her colleagues described a man with X-linked CGD who also had three other X-linked diseases. When his X-chromosome was examined, there was a small piece missing, indicating where on the X-chromosome all four of these disease-linked genes could be found.

In 1987, Dr. Stuart Orkin in the Howard Hughes Medical Institute at Harvard University and his colleagues used this information to isolate the X-linked CGD gene. Since then, three other CGD genes have been found on other chromosomes, making CGD four distinct genetic disorders. 

Daily doses of antibiotics reduce infections in people with CGD. Injections of interferon gamma, a potent immune system hormone, also reduce infections in these patients. Scientists used recombinant DNA technology to make useful amounts of this hormone from bacteria. While these treatments are not a cure for CGD, they have improved the outlook for people with CGD.

A gene therapy trial to treat a non-X-linked form of CGD started at NIH in July 1995. Immature white blood cells were purified from the blood of a person with CGD. The cells were treated with the normal gene, and put back into the same person. Five people with CGD were treated this way. Although only some corrected cells stayed in the bloodstream for several months, this effort represented an important step in developing gene therapy for CGD. This photo shows white blood cells from one of the people who received gene therapy. The dark cell has been corrected by the gene treatment. For more on gene therapy, click here.
  Photomicrograph of NBT test - Courtesy of Dr. Harry L. Malech and Dr. Douglas Kuhns, National Institute of Allergy and Infectious Diseases
Photograph of NBT test. Courtesy of Dr. Harry L. Malech and Dr. Douglas Kuhns, National Institute of Allergy & Infectious Diseases.

Breast Cancer

When cells become cancerous they divide rapidly and lose their normal function. The genes regulating cell division have stopped working properly. The mammogram shown here on the left shows normal breast tissue; the whitish area in the tissue on the right is cancerous.  It is also important to remember that having a defective gene does not mean that you are definitely going to get cancer -- it means that you have a higher risk of developing cancer.

normal vs. cancerous breast
Normal vs. Cancerous Breast. Courtesy of the National Cancer Institute.

Breast cancer cell -  A breast cancer cell as seen through an electron microscope - Courtesy of the National Cancer Institute
A breast cancer cell as seen through an electron microscope. Courtesy of the National Cancer Institute.


In October 1990, Dr. Mary-Claire Kingís team at the University of California at Berkeley announced that chromosome 17 carried the breast cancer gene called BRCA1. Their discovery set off a scramble to find the specific section of DNA containing the gene. 

In September 1994, a team led by Dr. Mark Skolnick of the University of Utah Medical Center, which included a group led by National Institute of Environmental Health Sciences scientist Dr. Roger Wiseman, announced the discovery of the BRCA1 gene.

Knowing the BRCA1 gene allows scientists to study the protein whose structure and function the gene governs. Is it not as active as it should be? Is it too active? Are necessary receptors not being formed? BRCA1 contributes only to 5%-10% of inherited breast cancers and may have a role in noninherited breast cancer when the BRCA1 protein somehow gets located in the wrong place. Other genes also are involved in breast cancer and need to be studied. The best way to detect breast cancer early is still regular mammograms.  Photo of a woman having a mammogram -  Courtesy of the National Cancer Institute
Woman having mammogram. Courtesy of the National Cancer Institute.
Photo of "No Cancer" button "No Cancer" button. Courtesy of the National Heart, Lung, and Blood Institute.   Gene therapy trials for all types of cancer are trying three different ideas: correcting the genes that normally prevent tumors but have mutated, increasing the bodyís immune defense to tumors, and altering normal cells to withstand higher doses of chemotherapy or altering cancer cells to become more sensitive to the drugs. For more on gene therapy, click here.


Heredity diagram
  BRCA1 is a dominant mutation linked to breast cancer.

Cystic Fibrosis (CF)

Cystic Fibrosis (CF) mainly affects peopleís lungs and digestive systems. A thick mucus prevents normal breathing and digestion, leading to infections and loss of the lungs' ability to function. Digestive enzyme supplements and antibiotics may help, and periodically the airway to the lungs may need clearing. Even so, half of the people with CF die by the age of 30. CF affects one in 2000-3000 Caucasian babies.

CF is a recessive trait.

Letter to Dr. Collins

Letter to Dr. Collins. Courtesy of the National HumanGenome Research Institute


  In 1989, the gene causing Cystic Fibrosis (CF) was discovered. By 1993, gene therapy trials to treat people with CF began. Today, researchers struggle to develop a safe, effective gene therapy, as well as other, more traditional therapies. Below is a timeline showing how fast genetic research can sometimes lead to new attempts to treat a disease.




CFTR color graphic  - Credit line: Celia Hooper, Journal of NIH Research, Nov-Dec. 1989

Celia Hooper, Journal of NIH Research, Nov-Dec. 1989.


Dr. Francis Collinsí team at the University of Michigan, and Drs. Lap-Chi Tsui and John Riordanís team at the University of Toronto locate the CF gene. The protein made from the instructions encoded by the gene is called CFTR (cystic fibrosis transmembrane-conductance regulator).



Dr. Michael Welshís team at the University of Iowa demonstrated what the protein called CFTR does in the human body. They added normal CFTR to CF cells which had been cultured in the laboratory. When normal CFTR was added, the chloride (salt) transport between the cell membranes began to function correctly.



  Photo of Dr. Crystal's gene therapy trial - Courtesy of the National Heart, Lung, and Blood Institute.
Dr. Crystal's gene therapy trial. Courtesy of the National Heart, Lung, and Blood Institute.
    When the safety and effectiveness of gene therapy had been proven as well as it could be in the laboratory and during studies in animals, the first human gene therapy trials for CF were conducted. Dr. Ronald Crystal, then of the National Heart, Lung, and Blood Institute, used copies of the normal CF gene to treat the lining of the nose and the lungs of people with CF (in this picture Dr. Crystal is third from the right). The trial tested how safe the procedure was for humans. Some people experienced inflammation in their lungs. Gene therapy trials to treat people with CF continue to take place in several places.



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