Some Basic Information About Genes
Some diseases in the kidneys are caused by problems (mutations) in genes. People have about 25,000-30,000 genes. The genes are made of DNA (deoxyribonucleic acid), a chemical that has four major types (or bases) which are abbreviated as A, T, G , and C. The sequence, or order, of these bases acts as a code to tell the body how to build proteins and how to maintain itself.
The genes are located together in a central place in cells called the nucleus, and are grouped together on long strands of DNA and protein that are called chromosomes. Most people have 46 chromosomes, with 23 coming from the mother, and another matched set of 23 coming from the father.
Most of the 25,000 – 30,000 genes come as pairs, with a person getting one copy from his/her mother and another copy from his/her father. (The exception to this are the genes that are located on the X and Y chromosomes. For these genes, there is usually only one copy.)Mutations are errors in the gene code that can affect the way that proteins are made and used in the body. These mutations can make it almost certain that a particular disease will happen, or they can just make it possible that the disease will happen. The types of mutations in a gene can also determine how severe the disease will be, and when it will show up in a person.
Some diseases can be caused by a mutation in just one of the two copies of a gene, with the mutated gene being strong enough to overcome the affects of the other, normal gene. This is called Autosomal Dominant Inheritance. An example of this is the disease Autosomal Dominant Polycystic Kidney Disease (ADPKD). If a person has an autosomal dominant genetic disease, it is likely that one of that person’s parents also had the disease, and also likely that some of that person’s children may inherit the disease.
Some diseases require a person to have mutations in both copies of a gene. This is called Autosomal Recessive Inheritance. In this case, having both copies of the gene with a mutation leaves the person without any normal protein from that gene, and leads to the disease. For these diseases, having one gene that is normal can cover up the mutation in the other gene and prevent the disease, or at least make it much less severe. Because of this, it is unlikely that parents or children of the affected person will have the disease. (If a parent or child has one copy of the gene with the mutation, they almost always will have a normal copy of the gene as well). An example is Autosomal Recessive Polycystic Kidney Disease.
Problems with genes found on the X chromosome are a little different. Since women have two X chromosomes and men have only one, any mutation in a gene on the X chromosome will be paired in women, but will be the only copy in men. This is why mutations in genes on the X chromosome usually affect only men, or at least affect men more severely than women. These types of diseases are called X-linked. An example of this kind of disease are many cases of Alport Syndrome.
In some cases, a person may inherit a gene with a mutation that usually leads to a disease, but never get that disease. This is an idea called penetrance. In these cases, it is thought that either other, unrelated genes that a person inherits can protect from developing the disease, or else both the mutation in the gene and some environmental exposure are required to get the disease, and the person without the disease just never had that environmental exposure.
While many diseases are known that are caused by mutations in a single gene, many other diseases seem to be caused by collections of minor mutations in many different genes. Diseases like this are more difficult to understand, as they often lead to a “risk” of developing the disease, and have many possible combinations of inherited genes, and therefore inherited risk. Most cases of high blood pressure (hypertension) and autoimmune diseases (like Lupus) likely fall into this category. How these types of diseases show up may also depend on what kind of environmental exposures a person has.
ADPKD is disease caused by a mutation in one of two kidney building block proteins, called polycystin 1 and polycystin 2 (genes PKD1 and PKD2). Specific mutations in either of these two genes cause abnormal fluid filled cysts to be formed in the kidney tissue. As these cysts grow in number and size, they press on other parts of the kidney, causing damage and scarring. Children can be born with severely enlarged kidneys (the size of normal adult kidneys) and can have immediate kidney failure at birth, but more commonly this is a condition that shows up in older children or adults, and may progress over several years to worse kidney disease and kidney failure. About half of the people with ADPKD will have kidney failure and require dialysis or transplant by the age of 50-60. ADPKD has also been associated with an increased chance of having brain aneurysms in some families, and with the development of liver disease.
ADPKD can show up as kidney failure or high blood pressure. It can also present as a kidney infection (when one of the cysts becomes infected), as pain from a cyst rupturing or bleeding, as enlarged kidneys found on routine examination, or when the person develops a kidney stone.
Diagnosis of ADPKD is usually made by ultrasound examination of the kidneys and the demonstration of large cysts in the kidneys. Before the age of 30, this diagnosis may be difficult, as cysts may not develop before then in more mildly affected people. There are studies going on that are looking at better ways to detect ADPKD earlier, and to predict which people will have rapid worsening of kidney function and which will likely have a better course, with little chance of developing problems.
As an autosomal dominant disease, the chance is that parents of an affected individual, as well as the children of the person, will carry the gene for the disease.
Currently genetic testing adds little to the diagnosis of a person with typical ADPKD, especially if the disease is already known to be in a certain family. In adults and some children, the diagnosis can usually be made by a kidney ultrasound, a general physical, and laboratory tests. While genetic testing of children in a affected family can reveal which child carries the gene and will likely have the disease as an adult, currently most doctors and genetic counselors do not recommend having children tested for diseases that have no specific early treatment and may only cause problems that are years away.
There is a new medication currently being tested, however, that may prevent or slow down the development of kidney damage in patients with ADPKD. If the tests of this medication show that it is helpful, then early detection of people with the disease may be important. For that, genetic tests to show who carries the gene will probably be the test of choice.
It is also possible that in the future, knowledge of which particular mutation a person carries in the PKD1 or PKD2 gene will help predict whether other ADPKD problems will develop.
ARPKD is disease caused by a mutation in a kidney building block protein called fibrocystin. The gene for this is named PKHD1. It is the only gene known to cause this particular problem, and a mutation in this gene is found in up to 90% of people with ARPKD. The mutation causes abnormal fluid filled cysts to be formed in the kidney tissue. As these cysts grow in number and size, they press on other parts of the kidney, causing damage and scarring. Children can be born with severely enlarged kidneys (the size of normal adult kidneys) and can have immediate kidney failure at birth, or the kidneys can be enlarged and working normally at birth, then progress over the next several years to worse kidney disease and kidney failure. Over half of children born with this will have kidney failure by the age of 10. High blood pressure is often a problem. Some children with particularly severe forms may be born with lungs that are too small for them to breath on there own. Some of these children may die in early infancy.
The disease also affects other parts of the body besides the kidney, most importantly the liver. Cysts and scarring of the liver may be a problem from early childhood, and may be the most severe problem in some children with ARPKD.
ARPKD is found in 1:20,000 – 1:40,000 newborns. Right now there are no specific cures for this disease.
How does genetic testing help?
Sometimes it is difficult to be sure a child has ARPKD. A few other diseases can look the same in a newborn child, and mild forms of the disease may not show up until later in childhood , and then may show up first by affecting the liver. A genetic test can confirm the presence of a mutation in the PKHD1 genes and confirm that the problem is ARPKD and not some other kidney problem that would need different monitoring or treatment.
Once a mutation in the PKHD1 gene is found in a family, then decisions can be made whether testing other family members would be helpful. In general, testing of other children who do not appear to have any problems is not suggested for rare, autosomal recessive genes.
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