Ciliary Genes in Renal Cystic Diseases

Abstract

Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.

Reproduction Function in Male Patients With Bardet Biedl Syndrome

“…We hypothesize that cyst formation in the male genital tract of BBS patients results from a physio-pathological mechanism similar to that described in polycystic kidney disease: cyst formation would result from a dysfunction of the dimer polycystin 1–polycystin 2 (PC1-PC2) ( 11 , 41 , 42 ), inducing excess cell growth, proliferation, and secretion. In accordance with a recent discussion about the role of BBS proteins in the cystogenesis ( 43 ), we presume that, in ciliated epididymal cells like in kidney cells, BBSome interacts with PC1 to stabilize the complex ( Fig. 2 ).…”

“…The AC VI produces cAMP stimulating AMPk pathway and PKA pathway which are resulting in a stimulation of cell proliferation and CFTR-linked chloride secretion respectively ( 42 ). BBSome of the primary cilia stabilizes the PC1 complex and allows a functional dimerization with PC2 ( 43 ). B: An anomaly of BBSome decreases the stability of PC1-PC2 dimer ( 43 ), resulting further in an insufficient Ca2+ intracytoplasmic concentration, an insufficient repression of AC VI and finally to an excessive cell proliferation and excretion of chloride and fluid through the CFTR.…”

“…BBSome of the primary cilia stabilizes the PC1 complex and allows a functional dimerization with PC2 ( 43 ). B: An anomaly of BBSome decreases the stability of PC1-PC2 dimer ( 43 ), resulting further in an insufficient Ca2+ intracytoplasmic concentration, an insufficient repression of AC VI and finally to an excessive cell proliferation and excretion of chloride and fluid through the CFTR. Excessive cell proliferation and excessive fluid secretion lead to cyst formation.…”

Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells

“…In line with these functions, there are a diverse and complex network of inputs essential for formation, maintenance and functioning of this organelle 9 . Loss of VHL results in a corresponding loss of primary cilia categorizing VHL as a ciliopathy—a growing collection of diseases characterized by absent/aberrant primary cilia 10 , 11 . Studies in primary human RCC tumors confirmed the loss of primary cilia in tumor tissue compared to adjacent parenchyma 12 .…”

Comprehensive strategy improves the genetic diagnosis of different polycystic kidney diseases

“…Hereditary polycystic kidney diseases (PKDs) exhibit clinical similarity and genetic diversity 1 and may affect organ development and growth in patients ranging from embryos to adults 2 . Polycystic kidney diseases originate from the cellular dysfunctions of chemo‐ and mechano‐sensations and fluid transport in renal tubules, 3 which correlate with numerous molecules.…”