Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease?

• Published in: Nature reviews. Genetics Vol. 6; no. 12; pp. 928 - 940
• Main Authors: Hildebrandt, Friedhelm, Otto, Edgar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2005; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Centrosome - metabolism; Cilia - metabolism; Evolution, Molecular; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Function; Genetic disorders; Genetics of eukaryotes. Biological and molecular evolution; Human Genetics; Humans; Kidney diseases; Kidney Diseases, Cystic - genetics; Kidney Diseases, Cystic - metabolism; Mutation; Pathogenesis; Phenotype; Plant diseases; Proteins; Proteins - genetics; Proteins - metabolism; review-article; Signal transduction; Signal Transduction - genetics; Species Specificity; Kidney disease; Urinary system disease; Pathogenic; Centrosome; Cilia
• ISSN: 1471-0056; 1471-0064
• DOI: 10.1038/nrg1727

Key Points The ciliary and centrosome hypothesis on the pathogenesis of cystic diseases of the kidney (CDK) states that the protein products (cystoproteins) of genes that are mutated in CDK in humans, mice or zebrafish are expressed in primary cilia, basal bodies or centrosomes of renal epithelial cells. We discuss the genetics and function of the genes that are mutated in CDK that have recently been identified and their resulting clinical phenotypes. Cystoproteins are involved in complex protein–protein interactions. Cystoproteins are located in the primary cilia, basal bodies or centrosomes of renal epithelial cells. The primary cilium is a sensory organelle that is highly conserved throughout evolution. Many cystoproteins interact with other cystoproteins directly or as members of a protein complex. Cystoproteins are highly conserved in evolution, with orthologues that are expressed in osmosensor ciliated neurons of Caenorhabditis elegans , and in intraflagellar transport (IFT) proteins of Chlamydomonas reinhardtii . Cystoproteins are expressed in several organ systems; mutants therefore give rise to CDK that have pleiotropic phenotypes, such as retinitis pigmentosa, anosmia, ataxia, liver fibrosis, situs inversus , cardiac defects, infertility and obesity. CDK phenotypes are subject to the effects of modifier genes and oligogenic inheritance. The cilia hypothesis of CDK has revolutionized studies into the pathogenesis of many genetic diseases. New therapeutic approaches towards treating CDK are being developed. Cystic kidney diseases are among the most frequent lethal genetic diseases. Positional cloning of novel cystic kidney disease genes revealed that their products (cystoproteins) are expressed in sensory organelles called primary cilia, in basal bodies or in centrosomes. Primary cilia link mechanosensory, visual, osmotic, gustatory and other stimuli to mechanisms of cell-cycle control and epithelial cell polarity. The ciliary expression of cystoproteins explains why many other organs might be also affected in patients with cystic kidney disease. Protein–protein interactions among cystoproteins, and their strong evolutionary conservation, provide a basis for a multidisciplinary approach to unravelling the novel signalling mechanisms that are involved in this disease group.