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Genetic mutations that can cause Polycystic Kidney Disease

Genetic mutations that can cause polycystic kidney disease

Posted by:

J.Hart and Dr.M.Raszek

Polycystic Kidney Disease (PKD) is a genetic disorder that mainly affects the kidneys. Both cause cysts to form making the kidneys (and other organs) swell up or deform, which can lead to renal failure.

Polycystic Kidney Disease can be caused by mutations to different genes, but it is not entirely understood how these mutations lead to disease development. If the specific genes (covered below) are mutated to disrupt proper biological functions, then such affected individuals will have a high risk of developing PKD.

Understanding the different types of genetic mutations that can lead to PKD is important in order to distinguish among the types and to understand the course and treatment of these disorders.


Types of Polycystic Kidney Disease

There are three types of Polycystic Kidney Disease: the infantile type, called Autosomal Recessive Polycystic Kidney Disease (ARPKD), the adult-onset type called Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Acquired Cystic Kidney Disease.


Autosomal Dominant Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney disease (ADPKD) is the cause of the most common types of cysts in the kidneys that cause this disorder, accounting for 90% of all PKD cases. It affects about half a million people in North America and Europe.

Image of Merogenomics post quote on ADPKD

ADPKD occurs when a person inherits a specific mutation from just one parent. Autosomal dominant is the term that used in all genetic diseases that materialize due to inheritance of mutated DNA from just a single parent. Genetic material is inherited from both parents. In the case of autosomal dominant diseases, inherited mutations from only one parent are enough to cause the condition. Signs and symptoms of Autosomal Dominant Polycystic Kidney disease typically do not show up until adulthood, but cysts in the kidney are often present from birth or childhood.

Symptoms include stomach swelling, or swelling and pain in both sides of the body below your rib cage. This is often worse when you are lying down, especially if it's on just one side of your chest.

People with ADPKD may develop the following:

  • High blood pressure
  • Anemia
  • Headaches
  • Sleep apnea
  • Trouble breathing or shortness of breath when you are lying down


Autosomal Recessive Polycystic Kidney Disease

With Autosomal Recessive Polycystic Kidney Disease (ARPKD), a person inherits mutated genetic material from both parents who have or are carriers of PKD. Autosomal recessive diseases are any genetic diseases produced only when mutated genetic material is inherited from both parents.

The symptoms of Autosomal Recessive Polycystic Kidney Disease are usually milder because it typically develops later in life, and fewer cysts occur in the kidneys. Signs include high blood pressure, enlarged liver or spleen due to fluid buildup from excessive amounts of urine, bladder infections, and abnormal heart rhythms.

People with ARPKD may develop the following:

  • Kidney problems including hypertension (high blood pressure) or kidney stones
  • Enlarged liver or spleen due to fluid buildup from excessive amounts of urine
  • Bladder infections
  • Abnormal heart rhythms


Acquired Cystic Kidney Disease (ACKD)

Acquired Cystic Kidney Disease is a result of chronic kidney disease and unlike the other types, it is not inherited. This is the most common cause of Polycystic Kidney Disease in individuals living with chronic renal failure or end-stage renal disease (ESRD). One's risk of ACKD increases with the number of years on dialysis treatment.

Symptoms of ACKD include:

  • Loss of appetite
  • Weight loss
  • Fatigue
  • Nausea and vomiting

Treatment for Acquired Cystic Kidney Disease includes medications to control blood pressure, which is caused by fluid buildup in the body due to excessive amounts of urine production.

Image of Merogenomics post quote on ACKD


Who does Polycystic Kidney Disease affect?

Polycystic Kidney Disease affects both children and adults. Individuals who have a family history of the condition are at an increased risk to develop it as well, but they do not necessarily need to inherit the same mutated allele from their parents in order to be affected by this disorder. Overall, about 500,000 people in the United States suffer from one of three forms of PKD.

Image of Merogenomics blog post quote on polycystic kidney disease


Complications of Polycystic Kidney Disease

Since PKD affects kidney function, it may also impact cardiovascular health and other systems. The kidneys are responsible for filtering the blood and regulating its hormone levels. This means that Polycystic Kidney Disease can lead to high lipid or cholesterol levels, which may increase the risk of heart attacks and strokes.

Many people with PKD have no symptoms initially, until they develop complications from the disease. Additional complications that may occur with Polycystic Kidney Disease may include:

  • Coronary artery disease — Coronary artery disease is a common cause of death in people with Polycystic Kidney Disease
  • High blood pressure or high cholesterol levels — Which may cause kidney damage or other cardiovascular complications
  • Proteinuria — Protein in the urine that may cause kidney damage
  • Edema — Swelling of feet, ankles, legs, hands and abdomen
  • Hearing loss — Due to a buildup of fluid around the inner ear chambers
  • Muscle cramps — Due to electrolyte imbalance


Genetic mutations that can cause ARPKD

For ARPKD, the mutations are in the PKHD1 gene, with one mutation inherited from each parent. Parents do not have to be affected by the disease, they merely have to be a carrier of a mutation, meaning they have to harbour a mutation in only one of their two copies of the PKHD1 gene. In such instance, a parent who is a carrier has a 50% chance of passing on the affected gene to their offspring. If the parent is also affected by the recessive disease, they will pass on the affected gene to the child for sure. Whether the child will develop the disease will depend if the second parent also passes on same mutated gene to same child. Thus if both parents are merely carriers, they will have combined chance of 25% that their child will be affected.

The PKHD1 gene is the DNA code that contains the instructions for making a fibrocystin protein. Proteins are the robots of the cells and together the concerted work of all the proteins in a cell gives life to a cell. This particular fibrocystin robot protein resides in kidney cells.

What does this kidney robot do?

We do not know! But we do know it resides in the cilia of kidney. Cilia are like living hair. Or think of a carpet, and imagine that every strand of that carpet hair is alive. Cilia is like that, a carpet of tentacles, used to massively expand the surface area of our organ that comes in contact with extracellular fluid (any fluid that is washing the outside of cells). The kidney renal tubules, where urine is formed, are lined with this living carpet of cilia.

But the link between the gene function and disease phenotype (observed disease symptoms) is obvious.

This fibrocystin robot protein is very interesting. It is a cell surface receptor, meaning this robot protein directly interacts with the outside world to which cells have to respond. Often the job of such cell surface receptors is to pass on information into the inside of the cell, telling the cell how to respond to the outside world. These responses can be dramatic in outcome. In order to relay the signal from outside to inside, these receptors span the cell wall and have components present on both the inside and outside of the cell. The fibrocystin protein is just such a receptor that relays the signal from the outside world to inside the cell. This is bound to be important.

Image of Merogenomics article quote on cell receptors

How mutations that affect the fibrocystin protein lead to cysts is not known. What is known is that all of the gene mutations in the PKHD1 gene appear to destroy the normal function of the fibrocystin protein receptor by affecting its structure. That makes sense if it is a receptor. Receptors are very sensitive to three-dimensional structural changes because they are already intricately shaped to recognize something floating about outside the cell. Usually, these floating molecules must be a very specific shape to bind to receptors. So change the receptor even a tiny bit and whatever floating molecule that was supposed to interact with this receptor, will no longer be able to bind it.


Genetic mutations that can cause ADPKD

Mutations of two genes, PKD1 and PKD2, which encode polycystin-1 and polycystin-2, respectively, are responsible for a majority of the genetically involved cases of ADPKD. What polycystin does is also not fully known but it does interact with polycystin-2 and it also spans the cell wall like fibrocystin. Interaction with polycystin-2 is necessary to relay signals from outside to inside, again like fibrocystin, so destruction of these proteins through genetic mutations once again affects proper communication that tells kidney cells how to properly respond to the outside world. They are also present in the cilia and are believed to tell the cells how to properly develop and subsequently function. Currently it is presumed that disruption of this function leads to abnormal cellular growth resulting in cysts. Mutations in the PDK1 gene are responsible for at least three quarters of all cases of ADPKD, whereas mutations in the PDK2 gene are responsible for up to 15 percent.

However, 10-15% of patients suspected of ADPKD actually have no PKD1 or PKD2 mutation at all. Recent studies have also identified multiple additional proteins, specifically those encoded by SEC63 and SEC61B genes, functioning in the endoplasmic reticulum, cause ADPKD by affecting how much of polycystin-1 is actually made. Even though polycystins might be fine, their amount is produced at such low levels, it becomes similar in impact to mutations in PKD1 or PKD2 genes.

In addition, patients can have a mutation in any combination of the proteins that function in the endoplasmic reticulum function, ALG8, ALG9, GANAB, PRKCSH, SEC61B, and SEC63, have been shown to have an overlap with ADPKD. The endoplasmic reticulum is a cellular internal factory involved in the production and processing of proteins to their final version prior to being released into the cell. Not surprisingly, the endoplasmic reticulum is located right next to the nucleus where the DNA resides with all of the encoded information for protein production.

Image of Merogenomics article quote on how are proteins made

Recall that for the ADPKD, you only need to inherit one mutated copy of genetic material from only one of your parents. It follows then, that for autosomal dominant conditions, it is genetically easier to create a disease through random mutations than it is for autosomal recessive conditions where two genetic locations have to be mutated instead of just one.

As a consequence, ADPKD can also be caused by spontaneous mutations early in the development of the affected individual. These spontaneous mutations are not inherited, they are random mistakes from DNA duplication whenever cells are needed to divide to produce an organ. Such spontaneous mutations are referred to as somatic mutations. If such a random mutation event happens early enough in the body's development, it can lead to a mutation being propagated throughout the entire body, as if it was actually inherited. Or it could just be present in only a portion of the body. When only a portion of the body is affected like that, it is referred to as somatic mosaicism. When a somatic mosaicism effect is large enough, meaning, enough of the body is affected by that mutation, it can develop into a disease.

Somatic mosaicism is another cause of ADPKD patients with no heritable mutations detected.

Image of Merogenomics article quote on spontaneous mutations


How is Polycystic Kidney Disease diagnosed and treated?

There's no cure yet for Polycystic Kidney Disease, but many treatments and procedures exist to slow its progress.

PKD is diagnosed with a physical examination and imaging tests, such as CT or MRI scans. Specialists use the results of these exams to determine whether kidneys are functioning properly; they may also measure how much fluid you have in your body by checking your blood pressure and performing other measurements.

Treatment for PKD includes changing your diet to help manage fluid levels and prevent kidney stones. You may also need dialysis, a machine that can clean the blood of wastes so they don't build up in your body; this treatment is necessary for people with severe PKD who are not able to adequately filter their own blood or produce urine on their own.

The key to healthy kidneys is staying active, eating healthy, and staying up-to-date on your doctor visits. If you have a history of Polycystic Kidney Disease in your family, or if you think you may be experiencing symptoms, talk to your doctor right away. He or she can schedule a DNA test and assess the severity of your symptoms and provide recommendations on how to manage PKD with lifestyle changes or medical treatments.


This article has been produced by Jenny Hart in collaboration with Merogenomics Inc. Jenny Hart is a contributing writer on behalf of Jenny has been a copy writer for several years and covers a wide range of topics in the health care sector ranging from kidney disease to maintaining diet and wellness. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.


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