Cilia in cystic kidney and other diseases

Pazour, Gregory J.; Quarmby, Lynne M.; Smith, Abigail O.; Desai, Paurav B.; Schmidts, Miriam

doi:10.1016/j.cellsig.2019.109519

Cited by 32 publications

(26 citation statements)

References 166 publications

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“…Defects in ciliogenesis, as well as in the ciliary structure and function, cause a diverse range of heterogeneous multisystem disorders with variable phenotypes and high mortality, termed "ciliopathies". Most ciliopathies are very rare conditions affecting less than 1 in 2000 individuals, often less than 1:100,0000 with the exception of autosomal dominant polycystic kidney disease, which affects up to 1 in 1000-2000 persons [4,107]. Over 30 different ciliopathies have been identified, with more than 200 associated genes [108][109][110].…”

Section: Ciliopathiesmentioning

confidence: 99%

Ciliary Dyneins and Dynein Related Ciliopathies

Antony

Brunner

Schmidts

2021

Cells

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Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel developments in the field.

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Section: Ciliopathiesmentioning

confidence: 99%

Ciliary Dyneins and Dynein Related Ciliopathies

Antony

Brunner

Schmidts

2021

Cells

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“…Cilia play crucial roles in the development of vertebrates. In some cell types, cilia are present only transiently during a critical point in development [ 36 ], and the spatiotemporal dysregulation of cilia can therefore affect the development of many organ systems, including the central nervous, sensory, cardiovascular, digestive, metabolic, and skeletal systems [ 8 , 14 , 37 , 38 ]. These complex multisystem developmental disorders are collectively termed ciliopathies ( Table 1 ).…”

Section: Roles Of Cilia In Ciliopathy and Cancermentioning

confidence: 99%

“…Cystic kidney disease is one of the main renal ciliopathies [ 36 , 76 ]. Renal tubular cells detect fluid flow through cilia.…”

Section: Roles Of Cilia In Ciliopathy and Cancermentioning

confidence: 99%

Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer

Shiromizu

Yuge

Kasahara

et al. 2020

IJMS

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Cilia are antenna-like structures present in many vertebrate cells. These organelles detect extracellular cues, transduce signals into the cell, and play an essential role in ensuring correct cell proliferation, migration, and differentiation in a spatiotemporal manner. Not surprisingly, dysregulation of cilia can cause various diseases, including cancer and ciliopathies, which are complex disorders caused by mutations in genes regulating ciliary function. The structure and function of cilia are dynamically regulated through various mechanisms, among which E3 ubiquitin ligases and deubiquitinases play crucial roles. These enzymes regulate the degradation and stabilization of ciliary proteins through the ubiquitin–proteasome system. In this review, we briefly highlight the role of cilia in ciliopathy and cancer; describe the roles of E3 ubiquitin ligases and deubiquitinases in ciliogenesis, ciliopathy, and cancer; and highlight some of the E3 ubiquitin ligases and deubiquitinases that are potential therapeutic targets for these disorders.

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“…Since PKHD1 was shown to localize to the primary cilium, a microtubule-based, hair-like structure that protrudes from the cell membrane and is thought to work as a critical sensory antenna [41], we set forth to investigate the ciliary phenotype of ARPKD URECs, as an additional investigation of the phenotype associated with these PKHD1 alleles. Immunofluorescence analysis of cilia structure revealed elongated primary cilia on ARPKD URECs compared to control cells (Fig.…”

Section: Investigation Of the Ciliary Phenotype In Arpkd Cellsmentioning

confidence: 99%

Use of patient derived urine renal epithelial cells to confirm pathogenicity of PKHD1 alleles

et al. 2020

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Background PKHD1 is the main genetic cause of autosomal recessive polycystic kidney disease (ARPKD), a hereditary hepato-renal fibrocystic disorder which is the most important cause of end-stage renal disease during early childhood. ARPKD can also present in adulthood with milder phenotypes. In this study, we describe a 24-year-old woman with atypical polycystic kidney, no family history of renal disease and no obvious extra-renal manifestations who was referred for genetic investigation. Methods We used a combination of next generation sequencing, Sanger sequencing and RNA and microscopy studies performed on urine-derived renal epithelial cells (URECs) to provide a genetic diagnosis of ARPKD. Results A next generation sequencing panel of cystic ciliopathy genes allowed the identification of two heterozygous sequence changes in PKHD1 (c.6900C > T; p.(Asn2300=) and c.7964A > C; p.(His2655Pro)). The pathogenicity of the synonymous PKHD1 variant is not clear and requires RNA studies, which cannot be carried out efficiently on RNA extracted from proband blood, due to the low expression levels of PKHD1 in lymphocytes. Using URECs as a source of kidney-specific RNA, we show that PKHD1 is alternatively spliced around exon 43, both in control and proband URECs. The variant p.(Asn2300=) shifts the expression ratio in favour of a shorter, out-of-frame transcript. To further study the phenotypic consequence of these variants, we investigated the ciliary phenotype of patient URECs, which were abnormally elongated and presented multiple blebs along the axoneme. Conclusions We confirm the power of URECs as a tool for functional studies on candidate variants in inherited renal disease, especially when the expression of the gene of interest is restricted to the kidney and we describe, for the first time, ciliary abnormalities in ARPKD patient cells.

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Cilia in cystic kidney and other diseases

Cited by 32 publications

References 166 publications

Ciliary Dyneins and Dynein Related Ciliopathies

Ciliary Dyneins and Dynein Related Ciliopathies

Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer

Use of patient derived urine renal epithelial cells to confirm pathogenicity of PKHD1 alleles

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