Polycyclic Kidney Disease is commonly called as PKD or PCKD and caused by a mistake in the DNA, the basic code of genetics in the body. Basic symptoms of PKD include multiple cysts growing in the kidneys which resemble a small circular ball filled with watery fluid. The cysts in kidney vary in size from pinhead to a radius of 2cm. As disease gets more progressed, each cyst gets bigger and bigger, making kidneys very large. The phenotype appearance of Polycyclic Kidney Disease is Kidneys looking like as if they have numerous small balls stuck together in it. Patients can have dangerously high blood pressure (hypertension), pain in the back or sides, blood in the urine (hematuria), continuous infections in urinary tract, kidney stones and heart valve abnormalities. They also have a high possibility of abnormal bulging (aneurysm) in a large blood vessel called the aorta or in ones at the base of the brain. In short words, PKD is a life-threatening disease. There are generally two types of this disease: Autosomal Dominant Polycyclic Kidney Disease (ADPKD) and Autosomal Recessive Polycyclic Kidney Disease (ARPKD). As it can be inferred from the names of these diseases, individuals with one mutant copy of the gene (PKD1 or PKD2) develop ADPKD and individuals with both copies of the mutated gene develop ARPKD. The occurrence of ADPKD is 1 to 2:1,000 live births and the occurrence of ARPKD is 1:20,000 live births. In fact, Polycyclic Kidney Disease is the most widespread life-threatening genetic disease, affecting about 12.5 million people in the world.
Mutations in the PKD1, PKD2, and PKHD1 genes cause polycystic kidney disease. Mutations in either the PKD1 or PKD2 gene can cause Autosomal Dominant Polycystic Kidney Disease (ADPKD). These genes provide instructions for making proteins, but their functions are not yet fully understood. Researchers believe that they are involved in transmitting chemical signals from outside the cell to the cell's nucleus. In normal circumstances, proteins work together to promote normal kidney development, organization, and function. Mutations in the PKD1 or PKD2 gene lead to the formation of thousands of cysts, which disturbs proper functions of the kidneys. People with mutations in the PKD2 gene, especially women, typically have a less severe form of the disease than people with PKD1 mutations. The signs and symptoms including a malfunction of kidney tend to appear later in people having a PKD2 mutation.
Mutations in the PKHD1 gene cause Autosomal Recessive Polycystic Kidney Disease (ARPKD). Same as the genes mentioned above, PKHD1 gene provides instructions for generating proteins whose exact function is also not known. Scientists have not found how mutations in the PKHD1 gene lead to the symptoms of polycystic kidney disease.
In the website http://pkdb.mayo.edu/cgi-bin/mutations.cgi, there is a mutation database for Autosomal Dominant Polycystic Kidney Disease (ADPKD). Here, we can find mutation types of each gene causing ADPKD: PKD1 and PKD2. In the case of PKD1, the most common mutation types are frameshift, IVS silent and synonymous. It is also shown that in all cases of frameshift, the clinical significance is ‘definitely pathogenic’; whereas in all cases of IVS silent and synonymous, the clinical significance is ‘likely neutral’. For PKD2, the most common mutation types are frameshift and nonsense. Both types of mutation lead to ‘definitely pathogenic’ clinical significance. It can be concluded that frameshift is the most common type of mutation causing Autosomal Dominant Polycyclic Kidney Disease and it leads to detrimental result.
From the basic concepts that I learned from AP Biology class, insertions and deletions, which are additions or losses of nucleotides in a gene, cause frameshift mutation that generate a serious malfunction. Nonsense is also one of the examples in which serious abnormalities occur. Regarding this in mind, we can easily understand that frameshift and nonsense, which is the most common mutation types of PKD2, lead to ‘definitely pathogenic’ result. On the other hand, we can find out that IVS silent, which is a lower category of silent, generates ‘likely neutral’ result. Considering that silent has no effect on amino acid sequence, the ‘likely neutral’ result of IVS silent is also understandable.
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