Autosomal dominant polycystic kidney autosomal recessive, disease ... Polycystic Kidney (Autosomal dominant and autosomal recessive polycystic kidney disease -ADPKD and ARPKD-) - Genes PKD1, PKD2 and PKHD1.
Polycystic kidney disease is a disorder that affects the kidneys and other organs. This is the most common inherited kidney disease in many countries with an incidence of 1 case per 500 to 1,000 live births and is the cause of 10% of cases of end stage renal disease. In general, the cysts develop in the kidneys and interfere with blood filtration capacity, but can also develop in other organs, especially the liver. The growth of cysts causes the kidneys larger, can cause renal failure. The most common complications of the disease include hypertension, back pain, hematuria, recurrent urinary tract infections, kidney stones, and heart valve abnormalities. In addition, people with this disease have an increased risk developing an aortic or blood vessels of the brain basis aneurysm. These aneurysms may rupture with fatal consequences.
There are two main clinical forms of polycystic kidney disease that differ from the usual age of onset and its pattern of inheritance. The autosomal dominant (ADPKD: Autosomal Dominant Polycystic Kidney Disease) have signs and symptoms usually begin in adulthood, although often renal cysts are present from birth or childhood. This autosomal dominant form, is divided into type 1 and type 2, depending on the genetic cause. Autosomal recessive form of the disease (ARPKD: Autosomal Recessive Polycystic Kidney Disease) is much more rare and often fatal. Signs and symptoms of this condition are usually evident at birth or early childhood.
Polycystic kidney disease is caused by mutations in the PKD1, PKD2 and PKHD1 genes.
The PKD1 gene, located on the short arm of chromosome 16 (16p13.3), encodes a protein called polycystin-1. This protein is most active in the kidney cells before birth. Although its exact function is not well understood, polycystin-1 appears to interact with a smaller protein called polycystin-2 (encoded by the gene PKD2). Polycystin-1 is located in the cytoplasmic membrane of kidney cells. This positioning of the protein allows it to interact with other proteins, carbohydrates and lipids from outside the cell, allowing intercellular interactions (cell-cell), and the interactions of cells with parenchymal matrix. When an external molecule binds to polycystin-1 on cell surface, the protein interacts with polycystin-2 to trigger a sequence of intracellular chemical reactions. Polycystin-1 and polycystin-2 act together to regulate growth and cell division (proliferation), cell movement (migration), interactions with other cells and cell apoptosis. Polycystin-1 to interact with polycystin-2 forms a complex acting as a flow sensor-dependent mechanism to regulate the differentiated state of renal tubular epithelial cells.
This gene has 46 exons spanning over 52 kb of genomic DNA on chromosome 16. Much of 5'gene (exons 1-33) is duplicated in at least 6 copies with more than 95% its sequence homologous with the gene (-HGs- homologous genes). These duplications difficult and you condition study methods of genetic alterations of this gene to amplify and sequence the original gene only, without making copies with HGS. They have identified at least 581 mutations in the PKD1 causing polycystic kidney disease. The mutations described so far have been: missense mutations (295), and cutting mutations -splicing- junction (43), small deletions (130), small insertions (57), insertion / small deletions (4), deletions higher ( 42), larger inserts / duplications (4) and complex rearrangements (6). These mutations are responsible for approximately 85% of cases of autosomal dominant disease ADPKD type 1, which is the most common type of disease. Most of these mutations result in an abnormally small version nonfunctional polycystin-1 protein. The altered protein, could not perform its signaling function inside the cell and in primary cilia. As a result, the cells lining the kidney tubules can grow and divide abnormally, leading to the growth of numerous cysts characteristic of polycystic kidney disease.
The PKD2 gene, located on the long arm of chromosome 4 (4q22.1), encodes polycystin-2 protein, found in the kidneys prior to birth and in many tissues. Although its exact function is not well understood, polycystin-2 can be regulated by polycystin-1. It appears to act as a transient receptor potential ion channel and regulates the concentration of intracellular Ca ++.
The 15 exons of this gene extends over 75 kb of genomic DNA, but do not have PKD1 duplications, so that their study does not involve difficulties. They have identified at least 131 mutations in the PKD2 gene causing the disease. The mutations described so far have been: missense mutations (50), and cutting mutations -splicing- connection (19), small deletions (42), small insertions (11), insertion / small deletions (4), deletions higher ( 2), and larger insertions / duplications (3). These mutations are responsible for about 15% of all cases of autosomal dominant disease ADPKD type 2. Most mutations result in the production of an abnormally small nonfunctional version of polycystin-2 protein, disrupting its interaction with polycystin -1 and, therefore, altering the signaling inside the cell and in primary cilia. As a result, the cells lining the kidney tubules can grow and divide abnormally, leading to the growth of numerous cysts characteristic of the disease.
The PKHD1, located on the short arm of chromosome 6 (6p12.2), encoding fibroquistina (or polyductine) protein present in fetal and adult kidney cells, and is also present in low concentrations in the liver and pancreas . This protein can act as a receptor, interacting with molecules of the cell for receiving signals that help the cell to respond to its environment. This protein may also be involved in adhesion, repulsion and cell proliferation.
They have identified at least 386 mutations in the gene responsible PKHD1 PKD autosomal recessive. The mutations described so far have been: missense mutations (268), and cutting mutations -splicing- junction (29), small deletions (53), small insertions (20), indels small (8) and larger deletions (8) . These mutations alter the structure and normal function of the protein fibroquistina, or lead to the synthesis of an abnormally small non - functional version of the protein. It could not determine how these genetic changes lead to the formation of numerous cysts characteristic of the disease. Mutations in this gene are associated with autosomal recessive disease (ARPKD: Autosomal Recessive Polycystic Kidney Disease).
Although polycystic kidney disease is usually a genetic disorder, a small percentage of cases are caused by genetic mutations. These cases are referred acquired polycystic kidney disease, which occurs most often in people with other types of kidney disease who have been treated for several years with hemodialysis.
Most cases of polycystic kidney disease have a pattern of autosomal dominant (ADPKD). Some cases have an autosomal recessive inheritance pattern (ARPKD). People with this condition are born with a mutated copy the PKD1 or PKD2 gene in every cell. In about 90% of cases, an affected person inherits the mutation from an affected parent. The remaining 10% of cases result from new mutations in one gene and occur in people with no history of disease in your family. Although an altered gene copy in each cell is sufficient to cause disease, an additional mutation in the second copy of the PKD1 or PKD2 gene can cause cysts grow faster and increase disease severity. The rate at which cysts enlarge and cause loss of renal function is very variable, and can be influenced by mutations in other genes have not yet been identified.
Polycystic kidney disease can also be inherited in an autosomal recessive pattern. Persons with this form of the disease have two copies of the altered gene in each cell PKHD1. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
The diagnosis of autosomal dominant polycystic kidney disease (ADPKD) is usually based on renal cystic phenotype and family history, which is simple in elderly patients. However, diagnosis can be problematic in young patients when imaging methods or ultrasound are inconclusive as family history of the disease is unknown. This is important when you are considering donating a kidney before 30 years of age. In these cases is keen genetic study. Genetic studies of the PKD1 gene should be performed by different methods to avoid the usual amplifying duplications 5'end (exons 1-33).
Tests in IVAMI: in IVAMI perform the detection of mutations associated with dominant polycystic kidney disease asutosómica (ADPKD) or autosomal recessive (ARPKD), by complete PCR amplification of the exons of PKD1 and PKD2 genes in autosomal dominant form , or PKHD1 in autosomal recessive, respectively, and subsequent sequencing. For autosomal dominant form, the genetic study of the PKD1 gene is done with the strategies to evitare detect duplications (HGS: Homologous genes) of exons 1 to 33.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).