Cilia and Polycystic Kidney Disease, Kith and Kin
Story Date: Tue, 17 Jun 2014 09:04:00 EDT
Article by Liwei Huang, MD, PhD, Assistant Professor of Medicine and Research Mentor of EVMS Nephrology Fellowship, and Joshua H. Lipschutz
Cilia are thin rod-like organelles found on the surface of human eukaryotic cells. First described by Anthony van Leeuwenhoek in 1675 (Dobell, 1932), they were originally defined by their motility, being structurally and functionally similar to eukaryotic flagella. In 1876 and 1898 (Langerhans,1876; Zimmermann, 1898), another class of cilia was described, the solitary (or nonmotile) cilia, which were renamed primary cilia in 1968 (Sorokin, 1968). Motile cilia/flagella have been studied for many years in single-celled organisms, such as protozoa, and important insights into the physiology and biochemistry of these organelles have resulted. However, despite the established anatomical presence of primary cilia in eukaryotic cells, until recently, little has been known about their specific function, and they had even been considered vestigial organelles (Webber and Lee,1975). Over the past decade, the primary cilium began to receive increasing attention, after it was discovered that proteins mutated in different forms of polycystic kidney disease (PKD) were tightly associated with primary cilia.
PKD is a group of genetic disorders characterized by the growth of numerous cysts in the kidney. Cysts are normal “building blocks” for epithelial organs, but abnormal regulation of cystogenesis in the kidney results in cystic kidney disease. Autosomal dominant PKD (ADPKD), which affects approximately 500,000 Americans and 12,000,000 people world wide, is the most common potentially lethal genetic disorder in humans (Grantham, 2001). Mutations in PKD1, the gene encoding polycystin-1, and PKD2, the gene encoding polycystin-2, have been identified as the cause of ADPKD (The International Polycystic Kidney Disease Consortium, 1995; Mochizuki et al., 1996). Autosomal recessive PKD (ARPKD), a severe form of PKD that presents primarily in infancy and childhood, is caused by a mutation in the polycystic kidney and hepatic disease1 (Pkhd1) gene (Zerres et al., 1994). Nephronophthisis, a form of PKD that is the most common genetic cause of renal failure through age 30, is caused by mutations in multiple (16 and counting) different nephronophthisis (NPHP) genes (Hildebrandt et al., 2009).
More and more evidence has accumulated showing that gene mutations resulting in structural or functional defects of the primary cilium cause PKD. For example, ADP-ribosylation factor–like protein 13b (Arl13b), a small GTPase of the Arf family, is highly enriched in cilia and is required for cilia formation. Knockdown of the Arl13b gene results in disorganized cilia structure and kidney cyst formation in zebrafish (Duldulao et al., 2009). Mutations in Arl13b in patients lead to the nephronophthisis form of PKD (Cantagrel et al., 2008). Another example is kinesin-like protein 3A (KIF3A), one of the subunits of the cilia motor protein, kinesin-2, which is essential for cilia formation. Inactivation of KIF3A in renal epithelia induced kidney cyst formation and severe PKD (Lin et al., 2003). Virtually all forms of PKD in human patients and animal models are associated with perturbations in renal primary cilia structure and/or function. Although maintenance of primary cilia structure and function appears to be key to preventing/treating PKD, it is not entirely clear how aberrant ciliogenesis promotes the disease.