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genetic renal cystic diseases

Friday 14 November 2003

Cystic diseases of the kidney are a group of monogenic kidney diseases. They are among the most frequent genetic lethal diseases in humans. 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.

- Autosomal dominant forms of CDK, the most prominent example of which is autosomal dominant polycystic kidney disease (ADPKD), are characterized by end-stage renal disease (ESRD) in adulthood.

- Autosomal recessive forms of CDK, such as nephronophthisis (NPHP) and autosomal recessive polycystic kidney disease (ARPKD), cause ESRD in childhood or adolescence. In addition, many forms of CDK appear as an element of clinical syndromes that involve many organ systems, such as Bardet-Biedl syndrome (BBS).


- polycystic kidney diseases (PKDs)

  • ADPKD (autosomal dominant polycystic kidney disease)
  • ARPKD (autosomal recessive polycystic kidney disease)

- juvenile nephronophtisis (NHPH)
- Joubert syndrome
- Bardet-Biel dysndrome (BBS)
- Alstrom syndrome
- orofaciodigital syndrome type 1 (OFD1)


- A dazzling axiom has recently emerged in 2005: The cilia and centrosome hypothesis of CKD pathogenesis. According this theroy, the products of all genes that are mutated in CKDs in humans, mice or zebrafish are expressed in primary cilia, basal bodies or centrosomes.

The cilia and centrosome hypothesis of CDK pathogenesis was proposed because of the striking expression pattern of the protein products (cystoproteins) of genes that are mutated in CDK of humans, mice or zebrafish. They localize to primary cilia, basal bodies or centrosomes of renal epithelial cells.

Many cystoproteins interact directly or are members of a protein complex together with other cystoproteins. They are expressed in many organ systems, thereby giving rise to CDK that have pleiotropic phenotypes. Importantly, they are highly conserved in evolution with orthologues that are expressed in osmosensor ciliated neurons of C. elegans, and in IFT proteins of C. reinhardtii.

- The first two genes that have been implicated in CDK, polycystic kidney disease 1 and 2 (PKD1 and PKD2), were identified by positional cloning. They encode the proteins polycystin 1 and 2, respectively, that over the years were shown to have a role in the cell-cell interaction and cell-cycle control of epithelial cells. Nevertheless, the mechanistic link between this function and the development of renal cysts remained elusive.

PKD1 and PKD2 are present in primary cilia of the mammalian kidney. These findings indicate a possible connection between proteins that are involved in vertebrate CDK (cystoproteins) and proteins that are expressed in cilia.

- More recently, mutations in inversin (INVS) have been identified as the cause of a recessive form of CDK, infantile nephronophthisis type 2 (NPHP2). The finding that inversin forms a protein complex with beta-tubulin, the main scaffold protein of primary cilia, emphasized again the role of primary cilia in the pathogenesis of CDK.

- In the wake of these findings a dazzling axiom has emerged (the ciliary hypothesis of CKDs): the products of all genes that are mutated in CDK in humans, mice or zebrafish are expressed in primary cilia, basal bodies or centrosomes.

- Pleiotropy through ciliary expression

A prominent feature of CKDs is that organs other than the kidney are also affected. This extensive pleiotropy has now found a potential explanation in the ciliary hypothesis of CKDs.

It is currently unclear, however, what determines the different degrees of organ involvement in patients with NPHP and BBS, and why fewer organs are affected in certain forms of CDK such as ADPKD and ARPKD.

Because many proteins are defective in CKDs, and as most of these proteins are part of functional protein complexes, tissue-specific redundancy of these functions is conceivable. Below we discuss the involvement of specific tissue functions in relation to organ systems.


- Anosmia and the olfactory epithelium

The ciliary and basal body hypothesis for the pathogenesis of BBS was recently used a priori to postulate that patients with BBS should have impaired function of the olfactory sensory cilia if sensory cilia are central to the pathogenesis.

Testing this hypothesis helped to reveal that about 37% of patients with BBS had anosmia, a symptom that has not previously been recognized as part of BBS.

- Liver fibrosis

NPHP and BBS are associated with liver fibrosis, whereas ARPKD is associated with bile-duct widening. Both of these phenotypes can be explained through the cilia hypothesis, because the epithelial cells that line the bile ducts (cholangiocytes) possess primary cilia.

- Central nervous system anomalies

Recent data might provide a link between oculomotor apraxia, Cogan type (which is associated with mutations in NPHP1 and NPHP4), cerebellar vermis hypoplasia (in JBTS) and mental retardation (in BBS) to proteins that are involved in microtubule-associated functions in neuronal axons.

Because mechanotransport along microtubules not only has a role in intraciliary and axonal transport, but also in axonal outgrowth, it is conceivable that defective axonal outgrowth might be causing these neurological phenotypes.

For example, malformations of the cerebellum and brain that occur in Joubert syndrome might be due to impaired axonal outgrowth, which is analogous to the lissencephaly phenotype that is caused by the centrosomal proteins LIS1 and doublecortin.

Interestingly, mutations in the gene that encodes the motor protein KIF3A (kinesin family member 3A), which has an important role in axonal transport, lead to cystic kideny disease (CKD) in mice.

- Testis and infertility

Impaired IFT and lack of sperm flagella have been described in mouse models of BBS. Male hypogonadism and infertility, which occurs in CDK in humans with BBS, might be due to the same molecular and cellular defects.

- Congenital cardiac malformations

Congenital cardiac malformations might be part of a heterotaxy syndrome that is caused by the same mechanism that leads to situs inversus. This is exemplified by mutations in INVS in infantile NPHP that results in both situs inversus and cardiac septal defects in humans, mice and zebrafish.

- Obesity, diabetes and bone changes

The mechanistic connection between basal body expression of BBS proteins and the phenotypes of obesity, diabetes and bone changes in humans with BBS is currently unclear. Interestingly, in the Bbs6 knockout mouse model obesity was associated with hyperphagia and decreased activity of mice.


- I. renal dysplasia
- II. polycystic kidney diseases (polycystic renal diseases)
- III. renal medullary cystic diseases (renal medullary cysts)
- IV. renal cortical cysts
- V. renal cysts in hereditary syndromes
- VI. neoplastic cysts
- VII. miscellaneous renal cysts


- cortical cysts
- medullary cysts
- diffuse cysts


- renal lobulation ?
- glomerulogenesis ?
- pyelocaliceal cavities ?
- ureteres: thin or dilated ?
- bladder: normal or dilated ?
- topography of the renal cysts

  • cortical renal cysts
  • medullary renal cysts
  • diffuse renal cysts

See also

- renal cysts
- renal cystic lesions
- renal cystic tumors
- cystoproteins


- Wilson PD, Goilav B. Cystic disease of the kidney. Annu Rev Pathol. 2007;2:341-68. PMID: 18039103

- Hildebrandt F, Otto E. Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nat Rev Genet. 2005 Dec;6(12):928-40. PMID: 16341073

- Witzgall R. New developments in the field of cystic kidney diseases. Curr Mol Med. 2005 Aug;5(5):455-65. PMID: 16101475

- Renal cystic disease of infancy: results of histochemical studies. A report of the Southwest Pediatric Nephrology Study Group. Verani R, Walker P, Silva FG. Pediatr Nephrol. 1989 Jan;3(1):37-42. PMID: 2702085v