Ciliopathies and the Kidney: A Review

McConnachie, Dominique J.; Stow, Jennifer L.; Mallett, Andrew

doi:10.1053/j.ajkd.2020.08.012

Cited by 144 publications

(121 citation statements)

References 105 publications

(113 reference statements)

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“…The PC is a microtubule-based, membrane-surrounded mechanochemical antenna [ 166 , 167 ] that acts as a flow sensor in the tubular epithelium [ 168 , 169 ], and a key regulator of cell division, differentiation and metabolism in all nucleated cells [ 170 , 171 , 172 ]. Ciliary defects are associated with a large set of severe diseases, so called ciliopathies, the prime examples of which are various forms of polycystic kidney disease (PKD) [ 173 , 174 , 175 , 176 ]. The PC is a dynamic organelle that develops from the basal body (BB) that arises from the membrane-anchored mother centriole as the cell leaves the cell cycle, and gets resorbed during cell cycle reentry.…”

Section: Targets Functions Actionsmentioning

confidence: 99%

MRTF: Basic Biology and Role in Kidney Disease

Miranda

Lichner

Szászi

et al. 2021

IJMS

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A lesser known but crucially important downstream effect of Rho family GTPases is the regulation of gene expression. This major role is mediated via the cytoskeleton, the organization of which dictates the nucleocytoplasmic shuttling of a set of transcription factors. Central among these is myocardin-related transcription factor (MRTF), which upon actin polymerization translocates to the nucleus and binds to its cognate partner, serum response factor (SRF). The MRTF/SRF complex then drives a large cohort of genes involved in cytoskeleton remodeling, contractility, extracellular matrix organization and many other processes. Accordingly, MRTF, activated by a variety of mechanical and chemical stimuli, affects a plethora of functions with physiological and pathological relevance. These include cell motility, development, metabolism and thus metastasis formation, inflammatory responses and—predominantly-organ fibrosis. The aim of this review is twofold: to provide an up-to-date summary about the basic biology and regulation of this versatile transcriptional coactivator; and to highlight its principal involvement in the pathobiology of kidney disease. Acting through both direct transcriptional and epigenetic mechanisms, MRTF plays a key (yet not fully appreciated) role in the induction of a profibrotic epithelial phenotype (PEP) as well as in fibroblast-myofibroblast transition, prime pathomechanisms in chronic kidney disease and renal fibrosis.

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Section: Targets Functions Actionsmentioning

confidence: 99%

MRTF: Basic Biology and Role in Kidney Disease

Miranda

Lichner

Szászi

et al. 2021

IJMS

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“…Ciliopathies are rare conditions that have emerged as a new challenge for worldwide researchers [ 19 ]. Alterations of ciliary motility can lead to a wide spectrum of specific diseases in humans, including, for example, sterility for defective sperm cilia and a condition known as “situs inversus”, in which internal organs are inverted due to defective embryonic cilia.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Spectrum of Kidney Ciliopathies

Santoni

Piva²,

Cimadamore

et al. 2020

Diagnostics

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Ciliopathies are a group of multi-organ diseases caused by the disruption of the primary cilium. This event leads to a variety of kidney disorders, including nephronophthisis, renal cystic dysplasia, and renal cell carcinoma (RCC). Primary cilium contributes to the regulation of the cell cycle and protein homeostasis, that is, the balance between protein synthesis and degradation by acting on the ubiquitin-proteasome system, autophagy, and mTOR signaling. Many proteins are involved in renal ciliopathies. In particular, fibrocystin (PKHD1) is involved in autosomal recessive polycystic kidney disease (ARPKD), while polycystin-1 (PKD1) and polycystin-2 (PKD2) are implicated in autosomal dominant polycystic kidney disease (ADPKD). Moreover, primary cilia are associated with essential signaling pathways, such as Hedgehog, Wnt, and Platelet-Derived Growth Factor (PDGF). In this review, we focused on the ciliopathies associated with kidney diseases, exploring genes and signaling pathways associated with primary cilium and the potential role of cilia as therapeutic targets in renal disorders.

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“…It is possible that TSPEAR phenotypes such as hearing loss and tooth agenesis show variable penetrance in subjects with different genetic backgrounds. For example, FGF3 polymorphisms have been associated with variable levels of tooth agenesis in prior cohorts (Vieira et al, 2013 ), while multilocus inheritance has been well documented in Bardet‐Biedl syndrome, where up to 23 loci have been identified that initiate or modify disease (McConnachie et al, 2020 ; McKusick‐Nathans Institute of Genetic Medicine, 2020 ). While polygenic inheritance is one potential explanation for differences in TSPEAR phenotype penetrance, it is also possible that more subtle findings such as nail dysplasia or tooth agenesis were overlooked during clinical evaluation.…”

Section: Discussionmentioning

confidence: 99%

TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study

Bowles

Ferrer

Nishimura

et al. 2021

American J of Med Genetics Pt A

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Biallelic loss-of-function variants in the thrombospondin-type laminin G domain and epilepsy-associated repeats (TSPEAR) gene have recently been associated with ectodermal dysplasia and hearing loss. The first reports describing a TSPEAR disease association identified this gene is a cause of nonsyndromic hearing loss, but subsequent reports involving additional affected families have questioned this evidence and suggested a stronger association with ectodermal dysplasia. To clarify genotype-phenotype associations for TSPEAR variants, we characterized 13 individuals with biallelic TSPEAR variants. Individuals underwent either exome sequencing or panel-based genetic testing. Nearly all of these newly reported individuals (11/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss. Of the individuals displaying hearing loss, all have additional variants in other hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype. When presented alongside previous reports, the overall evidence supports the association of TSPEAR variants with ectodermal dysplasia and tooth agenesis features but creates significant doubt as to whether TSPEAR variants are a monogenic cause of hearing loss. Further functional evidence is needed to evaluate this phenotypic association.

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Ciliopathies and the Kidney: A Review

Cited by 144 publications

References 105 publications

MRTF: Basic Biology and Role in Kidney Disease

MRTF: Basic Biology and Role in Kidney Disease

Exploring the Spectrum of Kidney Ciliopathies

TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study

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