ADPKD is caused by mutations (unintended change or typo) in two genes. Mutations of the first gene, PKD1, accounts for about 85 percent of patients affected by ADPKD, while mutations of the second gene, PKD2, account for the remaining patients. There are no other ADPKD genes that have been identified to date. The PKD1 and PKD2 genes encode the proteins polycystin-1 and polycystin-2, respectively. These two proteins interact to regulate cells in the kidneys and liver to maintain their orientation to form tubular structures as well as their growth and fluid secretion function. Mutations of the PKD1 or PKD2 gene leads to a wide array of cellular abnormalities associated with normal polycystin function and ultimately result in ADPKD.
There is a marked difference in kidney disease severity associated with mutations that inactivate the PKD1 compared to the PKD2 gene. Specifically, patients with inactivating PKD1 mutations have bigger kidneys, more kidney related complications and require dialysis at an earlier age compared to those with PKD2 mutations (55 versus 75 years, respectively). More recent studies have also identified a subset of PKD1 patients with milder kidney disease in which their mutations do not seem to completely inactivate polycystin-1 function; this is called a non-truncating PKD1 mutation.
Determining the specific gene mutation you have requires genetic testing. This type of testing is not typically covered by health insurance and could be costly (several thousand dollars). If you or someone you know chooses to explore this option, Athena Diagnostics was the first lab to begin PKD genetic testing and they continue to do so today.
How is ADPKD inherited?
The term “autosomal dominant” in ADPKD refers to two important features of the disease. First, because the disease genes reside on an autosome (i.e. PKD1 on chromosome 16 and PKD2 on chromosome 4), both male and female at-risk patients have an equal chance of inheriting ADPKD. This means that the possibility of transmitting ADPKD from an affected parent to a child is 1 in 2, or 50 percent (like flipping a coin) when a large number of families are studied. However, the number of affected children within a single family is entirely due to chance and may or may not be 50 percent. Second, the disease is dominant because inheritance of one copy of the mutated PKD1 or PKD2 gene from one parent is sufficient to cause disease.
Four to 10 percent of patients with ADPKD may have “de novo” disease due to a spontaneous mutation. Typically these patients do not have a family history of ADPKD. Their disease is due to a spontaneous mutation of the PKD1 or PKD2 gene in one of the germ cells (i.e. egg or sperm) of one of their parents that then gets passed on to them. Individuals with “spontaneous mutations” thus become the founders of a bloodline which is continued into the next generation with 50 percent chance of disease transmission. Most of your body cells carry one normal and one mutated copy of the ADPKD gene. However, when sperms or eggs are formed in that person, only one of the two copies of a ADPKD gene is passed on, typically with equal chance. Only the sperms or eggs that carry a mutated PKD gene can pass on the disease. Therefore, the chance of disease transmission to your children is typically 50 percent.
Will a person with a mutation for ADPKD always have the disease?
Yes, the genes for ADPKD are dominant, which means that inheriting only one mutated copy of the PKD1 or PKD2 gene from an affected parent is sufficient to cause the disease. There is no carrier state with a dominant disease, and it does not skip a generation. This means that the disease will eventually manifest as you get older and that all generations have the potential to be affected. If you have a mutation, at some point in your life at least some of the symptoms of the disease will probably occur, although they could be very mild. When an at-risk individual does not have a mutation for ADPKD, he/she is not affected and the disease cannot be passed to the next generation.
This does not mean that everyone who gets the ADPKD gene will have the same signs or symptoms or the same course of the disease. There is a wide spectrum of severity within ADPKD. At one end are children who are diagnosed before birth or in the first year of life with cysts or big kidneys, at the other end are people who have few symptoms, even when they are much older. It is important to note that some individuals (especially those with a PKD2 or non-inactivating PKD1 mutation) are more likely to live a normal life span and die of other causes before there is a need for dialysis or transplantation. A majority of patients with ADPKD will fall in the middle and at some point in their life will have some signs or symptoms associated with ADPKD.
Will everyone with a mutation in the same family have the same type of ADPKD?
Yes, all affected ADPKD patients with the same mutation in a family will have the same type of ADPKD. However, their signs, symptoms and course of the disease are often different. The most dramatic example of this occurs in families with children who are diagnosed before birth or in the first year of life. These children have symptoms long before their parents. Sometimes the parent may not even be aware they have ADPKD until after their child is diagnosed. Significant kidney disease variability within ADPKD families suggest other genetic and environmental factors can modify the severity of this disease.