Renal ciliopathies
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.
References (62)
- et al.
Monoallelic mutations to DNAJB11 cause atypical autosomal-dominant polycystic kidney disease
Am J Hum Genet
(2018) - et al.
Abnormalities in focal adhesion complex formation, regulation, and function in human autosomal recessive polycystic kidney disease epithelial cells
Am J Physiol Cell Physiol
(2010) - et al.
Mutations of ADAMTS9 cause nephronophthisis-related ciliopathy
Am J Hum Genet
(2019) - et al.
Mutations in MAPKBP1 cause juvenile or late-onset cilia-independent nephronophthisis
Am J Hum Genet
(2017) - et al.
Genomic analysis of Meckel-Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes
Eur J Hum Genet
(2013) - et al.
A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney
Development
(2004) - et al.
Pontin is essential for murine hematopoietic stem cell survival
Haematologica
(2012) - et al.
The SYSCILIA gold standard (SCGSv1) of known ciliary components and its applications within a systems biology consortium
Cilia
(2013) - et al.
Compound heterozygous mutations in the IFT140 gene cause Opitz trigonocephaly C syndrome in a patient with typical features of a ciliopathy
Clin Genet
(2016) - et al.
Expanding phenotype of nephronophthisis-related ciliopathy: an elderly patient with homozygous RPGRIP1L mutation
Nephron
(2018)
The nucleoside-diphosphate kinase NME3 associates with nephronophthisis proteins and is required for ciliary function during renal development
J Biol Chem
Autosomal dominant polycystic kidney disease: disrupted pathways and potential therapeutic interventions
J Cell Physiol
Steviol stabilizes polycystin 1 expression and promotes lysosomal degradation of CFTR and beta-catenin proteins in renal epithelial cells
Biomed Pharmacother
A human patient-derived cellular model of Joubert syndrome reveals ciliary defects which can be rescued with targeted therapies
Hum Mol Genet
In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery
Hum Mol Genet
Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10
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
Cited by (33)
Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis
2022, Kidney International ReportsCitation 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
Nucleoporin NUP205 plays a critical role in cilia and congenital disease
2021, Developmental BiologyCitation 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).
The entangled relationship between cilia and actin
2020, International Journal of Biochemistry and Cell BiologyCitation 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.
HOPS-dependent lysosomal fusion controls Rab19 availability for ciliogenesis in polarized epithelial cells
2024, Journal of Cell ScienceNPHP1 FULL DELETION CAUSES NEPHRONOPHTHISIS AND A CONE-ROD DYSTROPHY
2023, Retinal Cases and Brief Reports