Polycystin is a family of proteins with significant roles in the human body. They are involved in various cellular functions, contributing to the proper development and operation of organs. Dysfunction can lead to various health conditions, particularly affecting the kidneys. This article explores polycystin’s nature, normal roles, and how its dysfunction relates to kidney disease and other bodily systems.
Understanding Polycystin
Polycystin refers to a group of proteins, primarily polycystin-1 (PC1) and polycystin-2 (PC2), encoded by the PKD1 and PKD2 genes. PC1 is a large integral membrane glycoprotein, approximately 4303 amino acids long, with an estimated molecular mass of around 460 kDa. It possesses a substantial extracellular segment with domains facilitating protein-protein and protein-carbohydrate interactions, including 16 immunoglobulin-like PKD repeats, a receptor for egg-jelly (REJ) domain, and a G-protein-coupled receptor proteolytic site (GPS).
PC2 is a smaller integral membrane glycoprotein, about 110 kDa, composed of 968 amino acids. It is predicted to have six transmembrane domains and intracellular N- and C-termini. PC2 shares homology with the last six transmembrane domains of PC1. Together, PC1 and PC2 form a subfamily of transient receptor potential (TRP) channels. These proteins interact through their cytoplasmic coiled-coil domains, forming a complex that functions as a calcium-permeable receptor-channel.
Normal Cellular Functions of Polycystin
Polycystin proteins perform various functions important for healthy cellular processes. A significant role is their function as mechanosensors, particularly in the primary cilia of kidney tubule cells. Primary cilia are tiny, finger-like projections on the surface of most cells, including those lining renal tubules where urine is formed. Polycystin-1, located on these cilia, senses fluid flow through the tubules with its large extracellular domains, activating the calcium channels associated with polycystin-2.
This interaction regulates calcium influx into the cell, influencing various intracellular pathways. Proper calcium signaling maintains cellular homeostasis, influencing processes like cell growth and proliferation. Polycystin proteins also contribute to cell movement, interactions, and maintaining cell shape and polarity. These functions support the proper development and operation of organs, especially the kidneys, by ensuring tubules maintain their size and structure.
Polycystin and Polycystic Kidney Disease
Polycystin dysfunction is directly linked to polycystic kidney disease (PKD), a genetic disorder characterized by numerous fluid-filled kidney cysts. The most common forms are Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Recessive Polycystic Kidney Disease (ARPKD). ADPKD is more prevalent, affecting approximately 1 in 400 to 1,000 individuals. ADPKD is primarily caused by mutations in the PKD1 gene (about 85% of cases) or the PKD2 gene (about 15% of cases). ARPKD, a rarer and more severe form, results from mutations in the PKHD1 gene, coding for fibrocystin, another protein involved in cilia function.
In ADPKD, PKD1 or PKD2 mutations lead to non-functional polycystin proteins. The development of cysts often follows a “two-hit” mechanism, where a person inherits one mutated copy of the PKD gene, and a second, random mutation occurs in the remaining healthy copy of the gene in a specific kidney tubule cell. This “second hit” impairs functional polycystin in that cell, disrupting normal signaling through the primary cilium and triggering cyst formation.
Without functional polycystin, normal regulation of cell proliferation and fluid secretion becomes impaired. This leads to increased epithelial cell growth and excessive fluid accumulation within renal tubules, causing them to dilate and form cysts. These cysts progressively enlarge, replacing healthy kidney tissue and leading to kidney enlargement and declining kidney function. While cysts can begin forming in utero, ADPKD manifestations appear in adulthood, often around 30 to 40 years of age.
Disease severity varies; PKD1 mutations lead to more severe disease and earlier onset of end-stage kidney disease (around age 54), while PKD2 mutations are associated with a milder form and later onset (around age 74). Ultimately, this progressive cyst growth can result in chronic kidney disease and, for over 50% of ADPKD patients, end-stage kidney disease requiring dialysis or transplantation.
Polycystin’s Broader Presence and Functions Beyond the Kidneys
While polycystin dysfunction is most recognized for its kidney impact, polycystin proteins are present in various other organs and tissues. These include the liver, pancreas, heart, spleen, seminal vesicles, and brain arachnoid membranes. Their presence indicates a widespread role in maintaining cellular health.
Consequently, polycystin issues can lead to PKD manifestations beyond the kidneys. For instance, liver cysts are commonly found in adults with ADPKD, affecting over 90% of individuals over 35 years old. Pancreatic and seminal vesicle cysts are also observed. Polycystin proteins also help maintain blood vessel structural integrity; mutations can impair this, increasing susceptibility to cerebral aneurysms. Intracranial aneurysms occur in approximately 10% of individuals with ADPKD, a fivefold higher prevalence than in the general population, and can lead to serious complications if ruptured. Additionally, heart issues like mitral valve prolapse and aortic root dilation are associated with polycystin dysfunction.