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

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.

Abstract

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.

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Figure 1: Cystoproteins and their cellular functions.
Figure 2: The ciliary and centrosome hypothesis of renal cystic disease and related disorders.
Figure 3: Primary (non-motile) cilia of renal epithelial cells and connecting cilia of retinal photoreceptors are homologous structures.

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Acknowledgements

F.H. is supported by the US National Institutes of Health.

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Correspondence to Friedhelm Hildebrandt.

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DATABASES

Entrez Gene

AHI1

ALMS1

ARL6

BBS4

BBS5

CORS2

INVS

JBTS1

NPHP1

NPHP3

NPHP4

NPHP5

PCM1

PKD1

PKD2

PKHD1

TTC8

UMOD

OMIM

Alstrom syndrome

autosomal dominant polycystic kidney disease

autosomal recessive polycystic kidney disease

Bardet–Biedl syndrome

Caroli disease

Joubert syndrome

medullary cystic kidney disease 2

nephronophthisis

oculomotor apraxia, Cogan type

orofaciodigital syndrome type 1

Senior–Loken syndrome 1

Glossary

MODIFIER GENE

A gene that has quantitative effects on the phenotype that is controlled by another genetic locus.

ADHERENS JUNCTION

A cell–cell contact site of epithelial cells that contains the protein cadherin and is positioned just underneath the 'tight junction'.

FOCAL ADHESION

A cell–basement membrane cell-contact site of epithelial cells that contains the proteins α-integrin and β-integrin and has a role in signalling processes from the basement membrane to the cell nucleus.

STAND DOMAIN

A widespread class of P-loop NTPases. The signal transduction ATPases with numerous domains (STAND) have been found in proteins that are implicated in apoptosis, plant disease-resistance, pathogen response in animals and plants and transcriptional regulation in bacteria.

CILIARY TRANSITION ZONE

The region between the basal body and the axoneme of a cilium that is structurally not well-characterized.

AXONEME

The bundle of microtubules and other proteins that forms the core of each cilium or flagellum.

LISSENCEPHALY

'Smoothened brain'. A developmental defect of the brain in which the number of infoldings of the brain surface is reduced.

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Hildebrandt, F., Otto, E. Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease?. Nat Rev Genet 6, 928–940 (2005). https://doi.org/10.1038/nrg1727

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