Renal ciliopathies

doi:10.1016/j.gde.2019.07.005

Current Opinion in Genetics & Development

Volume 56, June 2019, Pages 49-60

https://doi.org/10.1016/j.gde.2019.07.005 Get rights and content

Renal ciliopathies are a group of disorders characterised by nephronophthisis, cystic kidneys or renal cystic dysplasia whose underlying disease pathogenesis is related to abnormal structure or function of the primary cilia complex. The number of renal ciliopathies continues to expand as genomic and genetic approaches identify novel causes. This in turn provides new opportunities to explore disease mechanisms and therapeutic approaches to target cystic kidney disease and other associated phenotypes. Here we review recent advances in the field of renal ciliopathies and how these allow new insights into this fascinating spectrum of diseases.

Introduction

Cilia are microtubule-based structures that protrude from the surface of almost every cell type in the human body. Cilia can be motile and be part of multi-ciliated structures, or can be immotile, located as a solitary projection on the cell. Examples of motile cilia include the multi-ciliated cells lining the respiratory tract and the fallopian tube which beat in organised waves to move mucus or debris and the ovum respectively [1].

Immotile cilia, known as primary cilia, act as a cellular antenna co-ordinating cell signaling, polarity and other sensory and functional roles. Within the kidney, renal tubular cells exhibit primary cilia which project into the lumen of the nephron. Structurally, primary cilia consist of a basal body, a transition zone and a ciliary axoneme, which is highly conserved throughout many species. Mutations in genes encoding components of the primary cilium lead to a diverse group of multi-system diseases, known as ciliopathies. Ciliopathies in which the mutations lead to renal disease, are known as a renal ciliopathies [2^•]. The range of phenotypes associated with renal ciliopathies includes nephronophthisis (NPHP), cystic kidney disease and renal cystic dysplasia, often with renal interstitial fibrosis. Importantly, in renal ciliopathies extra renal features are often part of the patient phenotype and relate to cilia dysfunction in other tissues, most frequently the retina and brain. There is a growing list of these multi-system ciliopathies, including Meckel Gruber Syndrome, Joubert Syndrome, Jeune syndrome and Bardet Biedl syndrome [2^•].

The purpose of this review is to combine recent molecular, genetic and mechanistic studies concerning renal ciliopathies as a means of updating a working biomedical and clinical knowledge on the topic. In highlighting new genetic renal ciliopathy disorders we will emphasise their contribution in terms of genotype, phenotype or mechanisms of disease.

Section snippets

Recent gene discoveries in renal ciliopathies

Inherited renal ciliopathies include autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive diseases such as nephronophthisis and autosomal recessive polycystic kidney disease (ARPKD). X-linked disorders, such as oral-facial-digital syndrome secondary to OFD1 mutations, are also part of the renal ciliopathy spectrum.

Several novel genes have recently been identified to cause renal ciliopathy syndromes including atypical forms of ADPKD, ARPKD-like syndromes and multisystem

Renal ciliopathy clinical trials

There are currently no curative treatments for renal ciliopathy syndromes, such as NPHP, Joubert syndrome, ARPKD and ADPKD. There are however, multiple clinical trials presently ongoing and a brief update of some of the key trials is given below.

ADPKD remains an active area of study. Vasopressin receptor inhibitors, such as tolvaptan, continue to be studied to determine their role in slowing cystic kidney growth in ADPKD. Tolvaptan is the first disease modifying drug to be licenced for the

Preclinical drug studies

There is a huge amount of recent preclinical data concerning putative treatments for cystic kidney disease and related ciliopathies. Cell, zebrafish and murine models have been exploited to explore novel therapeutic agents for renal ciliopathies. A few examples are discussed below.

Steviol, a metabolite of the stevioside sweetener, has been demonstrated to reduce cyst growth in polycystic kidney disease (PKD) murine models, by reducing expression levels and promoting lysosomal degradation of

Conclusions

It is clear that the field of renal ciliopathies is rapidly evolving. With each new gene discovery comes the opportunity to identify novel genetic mechanisms. The use of WES strategies will ensure that genes continue to be identified; however, there needs to be a shift towards moving ciliopathy genetics into mainstream medicine such that all patients with cystic kidney disease phenotypes can receive, where possible, a genetic diagnosis. In addition to genetic studies, molecular studies in

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

JAS is funded by The Medical Research Council (Award MR/M012212/1), Kidney Research UK and Northern Counties Kidney Research Fund. LAD is funded by Medical Research Council Discovery Medicine North Doctoral Training Partnership and Northern Counties Kidney Research Fund.

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Cited by (33)

Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis
2022, Kidney International Reports
Citation Excerpt :
However, in a subsequent multivariate approach adjusted for each individual factor, only the impact of arterial hypertension remained significant with an annual GFR loss of 7.0 ± 0.5 versus 4.6 ± 0.4 ml/min per 1.73 m2 BSA (P < 0.01). Since the identification of a large homozygous 290 kb deletion covering the entire NPHP1 gene in the 1990s,7 tremendous progress has been made in the molecular understanding of NPH and related ciliopathies.1,37–41 However, the focus of most scientific efforts has been on the discovery of the genetic background and molecular pathways.5,7,9,42
Nephronophthisis (NPH) comprises a group of rare disorders accounting for up to 10% of end-stage kidney disease (ESKD) in children. Prediction of kidney prognosis poses a major challenge. We assessed differences in kidney survival, impact of variant type, and the association of clinical characteristics with declining kidney function.
Data was obtained from 3 independent sources, namely the network for early onset cystic kidney diseases clinical registry (n = 105), an online survey sent out to the European Reference Network for Rare Kidney Diseases (n = 60), and a literature search (n = 218).
A total of 383 individuals were available for analysis: 116 NPHP1, 101 NPHP3, 81 NPHP4 and 85 NPHP11/TMEM67 patients. Kidney survival differed between the 4 cohorts with a highly variable median age at onset of ESKD as follows: NPHP3, 4.0 years (interquartile range 0.3–12.0); NPHP1, 13.5 years (interquartile range 10.5–16.5); NPHP4, 16.0 years (interquartile range 11.0–25.0); and NPHP11/TMEM67, 19.0 years (interquartile range 8.7–28.0). Kidney survival was significantly associated with the underlying variant type for NPHP1, NPHP3, and NPHP4. Multivariate analysis for the NPHP1 cohort revealed growth retardation (hazard ratio 3.5) and angiotensin-converting enzyme inhibitor (ACEI) treatment (hazard ratio 2.8) as 2 independent factors associated with an earlier onset of ESKD, whereas arterial hypertension was linked to an accelerated glomerular filtration rate (GFR) decline.
The presented data will enable clinicians to better estimate kidney prognosis of distinct patients with NPH and thereby allow personalized counseling.
Nucleoporin NUP205 plays a critical role in cilia and congenital disease
2021, Developmental Biology
Citation Excerpt :
Ciliopathies are a group of diseases characterized by genetic mutations that result in either abnormal formation or function of cilia (Braun and Hildebrandt, 2017). Since cilia are a component of nearly all cells in developing vertebrate organisms, cilia dysfunction results in pathologies that include hydrocephalus, polycystic kidney disease, retinal dystrophy, as well as congenital heart disease (CHD) (Bachmann-Gagescu and Neuhauss, 2019; Chaudhry and Henderson, 2019; Devlin and Sayer, 2019; Park et al., 2019). Advances in human genomics have led to the identification of numerous CHD candidate genes (Fakhro et al., 2011; Homsy et al., 2015; Jin et al., 2017).
Ciliopathies affect a variety of tissues during development including the heart, kidneys, respiratory tract, and retina. Though an increasing number of monogenic causes of ciliopathies have been described, many remain unexplained. Recently, recessive variants in NUP93 and NUP205 encoding two proteins of the inner ring of the nuclear pore complex were implicated as causes of steroid resistant nephrotic syndrome. In addition, we previously found that the inner ring nucleoporins NUP93 and NUP188 function in proper left-right patterning in developing embryos via a role at the cilium. Here, we describe the role of an additional inner ring nucleoporin NUP205 in cilia biology and establishment of normal organ situs. Using knockdown in Xenopus, we show that Nup205 depletion results in loss of cilia and abnormal cardiac morphology. Furthermore, by transmission electron microscopy, we observe a loss of cilia and mispositioning of intracellular ciliary structures such as basal bodies and rootlets upon depleting inner ring nucleoporins. We describe a model wherein NUP93 interacting with either NUP188 or NUP205 is necessary for cilia. We thus provide evidence that dysregulation of inner ring nucleoporin genes that have been identified in patients may contribute to pathogenesis through cilia dysfunction.
The entangled relationship between cilia and actin
2020, International Journal of Biochemistry and Cell Biology
Citation Excerpt :
In line with this, ALMS1 fibroblasts show abnormalities in actin stress fibre morphology (Collin et al., 2012). One of the most critical clinical features affecting ciliopathy patients is kidney disease (Devlin and Sayer, 2019). So far, several studies have shown that actin disorganisations contributes to ciliopathy-related kidney diseases.
Primary cilia are microtubule-based sensory cell organelles that are vital for tissue and organ development. They act as an antenna, receiving and transducing signals, enabling communication between cells. Defects in ciliogenesis result in severe genetic disorders collectively termed ciliopathies. In recent years, the importance of the direct and indirect involvement of actin regulators in ciliogenesis came into focus as it was shown that F-actin polymerisation impacts ciliation. The ciliary basal body was further identified as both a microtubule and actin organising centre. In the current review, we summarize recent studies on F-actin in and around primary cilia, focusing on different actin regulators and their effect on ciliogenesis, from the initial steps of basal body positioning and regulation of ciliary assembly and disassembly. Since primary cilia are also involved in several intracellular signalling pathways such as planar cell polarity (PCP), subsequently affecting actin rearrangements, the multiple effectors of this pathway are highlighted in more detail with a focus on the feedback loops connecting actin networks and cilia proteins. Finally, we elucidate the role of actin regulators in the development of ciliopathy symptoms and cancer.
HOPS-dependent lysosomal fusion controls Rab19 availability for ciliogenesis in polarized epithelial cells
2024, Journal of Cell Science
Primary cilia are sensory cellular organelles crucial for organ development and homeostasis. Ciliogenesis in polarized epithelial cells requires Rab19-mediated clearing of apical cortical actin to allow the cilium to grow from the apically docked basal body into the extracellular space. Loss of the lysosomal membrane-tethering homotypic fusion and protein sorting (HOPS) complex disrupts this actin clearing and ciliogenesis, but it remains unclear how the ciliary function of HOPS relates to its canonical function in regulating late endosome–lysosome fusion. Here, we show that disruption of HOPS-dependent lysosomal fusion indirectly impairs actin clearing and ciliogenesis by disrupting the targeting of Rab19 to the basal body, and that this effect is specific to polarized epithelial cells. We also find that Rab19 functions in endolysosomal cargo trafficking in addition to having its previously identified role in ciliogenesis. In summary, we show that inhibition of lysosomal fusion leads to the abnormal accumulation of Rab19 on late endosomes, thus depleting Rab19 from the basal body and thereby disrupting Rab19-mediated actin clearing and ciliogenesis in polarized epithelial cells.
Comprehensive analysis of pain genes in prognosis of kidney renal clear cell carcinoma and tumor immunotherapy: A comprehensive bioinformatic study
2024, Health Science Reports
NPHP1 FULL DELETION CAUSES NEPHRONOPHTHISIS AND A CONE-ROD DYSTROPHY
2023, Retinal Cases and Brief Reports

View all citing articles on Scopus

View full text

Renal ciliopathies

Introduction

Section snippets

Recent gene discoveries in renal ciliopathies

Renal ciliopathy clinical trials

Preclinical drug studies

Conclusions

Conflict of interest statement

References and recommended reading

Acknowledgements

Am J Hum Genet

Am J Physiol Cell Physiol

Am J Hum Genet

Am J Hum Genet

Eur J Hum Genet

Development

Haematologica

Cilia

Clin Genet

Nephron

J Biol Chem

J Cell Physiol

Biomed Pharmacother

Hum Mol Genet

Hum Mol Genet

Nat Med

Ciliopathies

Cold Spring Harb Perspect Biol

Many genes-one disease? Genetics of Nephronophthisis (NPHP) and NPHP-associated disorders

Front Pediatr

Diagnostic utility of exome sequencing for kidney disease

N Engl J Med

Growth pattern of kidney cyst number and volume in autosomal dominant polycystic kidney disease

Clin J Am Soc Nephrol

Mutations in GANAB, encoding the glucosidase IIalpha subunit, cause autosomal-dominant polycystic kidney and liver disease

Am J Hum Genet

Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease

Nat Genet

ARL3 mutations cause joubert syndrome by disrupting ciliary protein composition

Am J Hum Genet

Identification of a novel ADAMTS9/GON-1 function for protein transport from the ER to the Golgi

Mol Biol Cell

A CRISPR-based screen for Hedgehog signaling provides insights into ciliary function and ciliopathies

Nat Genet

Characterizing the morbid genome of ciliopathies

Genome Biol

A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy

Clin Genet

An Amish founder variant consolidates disruption of CEP55 as a cause of hydranencephaly and renal dysplasia

Eur J Hum Genet

A truncating mutation in CEP55 is the likely cause of MARCH, a novel syndrome affecting neuronal mitosis

J Med Genet

OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome

Hum Mol Genet

Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies

Sci Rep