bims-bicyki 2022-08-28 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–08–28
twelve papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Perspectives on Drug Development in Autosomal Recessive Polycystic Kidney Disease.
CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation.
Delay in funding of tolvaptan for polycystic kidney disease in Aotearoa New Zealand.
Molecular Diagnostics of Ciliopathies and Insights Into Novel Developments in Diagnosing Rare Diseases.
Cytoskeletal networks in primary cilia: Current knowledge and perspectives.
ENDOTHELIUM-SPECIFIC DEFICIENCY OF POLYCYSTIN-1 PROMOTES HYPERTENSION AND CARDIOVASCULAR DISORDERS.
[Analysis of PKD1 gene mutation in a pedigree affected with autosomal dominant polycystic kidney disease].
IMPACT OF AQUAPORIN-3, AQUAPORIN-7 AND HEPARANASE GENETIC POLYMORPHISMS ON AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE PROGRESSION.
A Common Intronic Single Nucleotide Variant Modifies PKD1 Expression Level.
Drug Development for Cystic Kidney Diseases.
The DYF-5 RCK and CDKL-1 CDKL5 kinases contribute differentially to shape distinct sensory neuron cilia morphologies in C. elegans.
GJA1 depletion causes ciliary defects by affecting Rab11 trafficking to the ciliary base.

Clin J Am Soc Nephrol. 2022 Aug 23. pii: CJN.04870422. [Epub ahead of print]

Perspectives on Drug Development in Autosomal Recessive Polycystic Kidney Disease.

Max C Liebau, Erum A Hartung, Ronald D Perrone.



Keywords:  ADPKD; ARPKD; PKD; PKHD1; drug development; fibrocystin; genetic kidney diseases

DOI:  https://doi.org/10.2215/CJN.04870422
J Mol Cell Biol. 2022 Aug 24. pii: mjac050. [Epub ahead of print]

CaMK4 overexpression in polycystic kidney disease promotes mTOR-mediated cell proliferation.

Yan Zhang, Emily A Daniel, July Metcalf, Yuqiao Dai, Gail A Reif, Darren P Wallace.

  Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of fluid-filled cysts causing nephron loss and a decline in renal function. Mammalian target of rapamycin (mTOR) is overactive in cyst-lining cells and contributes to abnormal cell proliferation and cyst enlargement; however, the mechanism for mTOR stimulation remains unclear. We discovered that calcium/calmodulin-dependent kinase IV (CaMK4), a multifunctional kinase, is overexpressed in the kidneys of ADPKD patients and polycystic kidney disease (PKD) mouse models. In human ADPKD cells, CaMK4 knockdown reduced mTOR abundance and the phosphorylation of ribosomal protein S6 kinase (S6K), a downstream target of mTOR. Pharmacologic inhibition of CaMK4 with KN-93 reduced phosphorylated S6K and S6 levels and inhibited cell proliferation and in vitro cyst formation of ADPKD cells. Moreover, inhibition of calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ) and calmodulin (CaM), two key upstream regulators of CaMK4, also decreased mTOR signaling. The effects of KN-93 were independent of the LKB1-AMPK pathway and the combination of KN-93 and metformin, an AMPK activator, had additive inhibitory effects on mTOR signaling and in vitro cyst growth. Our data suggest that increased CaMK4 expression and activity contribute to mTOR signaling and proliferation of cystic cells of ADPKD kidneys.

Keywords:  ADPKD; AMP kinase; CaMK4; CaMKKβ; LKB1; calmodulin

DOI:  https://doi.org/10.1093/jmcb/mjac050
N Z Med J. 2022 Aug 05. 135(1559): 112-117

Delay in funding of tolvaptan for polycystic kidney disease in Aotearoa New Zealand.

Tracy Chan, Walter van der Merwe, Janak R de Zoysa.

Autosomal dominant polycystic kidney disease (ADPKD) is the fifth most common cause of end stage kidney disease (ESKD) in Aotearoa New Zealand. Identification of two genes, PCKD1 and PCKD2, which cause the majority of this disease, has played a key role in the development of DNA-sequence molecular diagnostics. ADPKD is characterised by the formation and growth of multiple cysts within the kidney, with some but not all patients progressing to ESKD. The diagnosis of ADPKD is based on the presence of family history, and radiological imaging although increasingly genetic testing is being used for screening and diagnosis. Once diagnosed, standard management of ADPKD includes laboratory monitoring of chronic kidney disease (CKD) parameters, lowering of blood pressure, and a high fluid intake. Over the last decade much research has been undertaken for targeted therapies for ADPKD; however, despite funding of these medications overseas since May 2015, and applications to Te Pātaka Whaioranga, The Pharmaceutical Management Agency (PHARMAC), these therapies remain unavailable to New Zealanders resulting in an increased burden of disease to individuals and the whānau and financial cost to the health system.
Br J Biomed Sci. 2022 ;79 10221

Molecular Diagnostics of Ciliopathies and Insights Into Novel Developments in Diagnosing Rare Diseases.

K Modarage, S A Malik, P Goggolidou.

  The definition of a rare disease in the European Union describes genetic disorders that affect less than 1 in 2,000 people per individual disease; collectively these numbers amount to millions of individuals globally, who usually manifest a rare disease early on in life. At present, there are at least 8,000 known rare conditions, of which only some are clearly molecularly defined. Over the recent years, the use of genetic diagnosis is gaining ground into informing clinical practice, particularly in the field of rare diseases, where diagnosis is difficult. To demonstrate the complexity of genetic diagnosis for rare diseases, we focus on Ciliopathies as an example of a group of rare diseases where an accurate diagnosis has proven a challenge and novel practices driven by scientists are needed to help bridge the gap between clinical and molecular diagnosis. Current diagnostic difficulties lie with the vast multitude of genes associated with Ciliopathies and trouble in distinguishing between Ciliopathies presenting with similar phenotypes. Moreover, Ciliopathies such as Autosomal Recessive Polycystic Kidney Disease (ARPKD) and Meckel-Gruber syndrome (MKS) present with early phenotypes and may require the analysis of samples from foetuses with a suspected Ciliopathy. Advancements in Next Generation Sequencing (NGS) have now enabled assessing a larger number of target genes, to ensure an accurate diagnosis. The aim of this review is to provide an overview of current diagnostic techniques relevant to Ciliopathies and discuss the applications and limitations associated with these techniques.

Keywords:  cilia; ciliopathies; polycystic kidney disease; rare disease; whole exome sequencing

DOI:  https://doi.org/10.3389/bjbs.2021.10221
J Cell Physiol. 2022 Aug 24.

Cytoskeletal networks in primary cilia: Current knowledge and perspectives.

Ruixin Ge, Minghui Cao, Miao Chen, Min Liu, Songbo Xie.

  Primary cilia, microtubule-based protrusions present on the surface of most mammalian cells, function as sensory organelles that monitor extracellular signals and transduce them into intracellular biochemical responses. There is renewed research interest in primary cilia due to their essential roles in development, tissue homeostasis, and human diseases. Primary cilia dysfunction causes a large spectrum of human diseases, collectively known as ciliopathies. Despite significant advances in our understanding of primary cilia, there are still no effective agents for treating ciliopathies. Primary ciliogenesis is a highly ordered process involving membrane trafficking, basal body maturation, vesicle docking and fusion, transition zone assembly, and axoneme extension, in which actin and microtubule networks play critical and multiple roles. Actin and microtubule network architecture, isotropy, and dynamics are tightly controlled by cytoskeleton-associated proteins, a growing number of which are now recognized as responsible for cilium formation and maintenance. Here we summarize the roles of actin and microtubules and their associated proteins in primary ciliogenesis and maintenance. In doing so, we highlight that targeting cytoskeleton-associated proteins may be a promising therapeutic strategy for the treatment of ciliopathies.

Keywords:  actin; ciliopathy; cytoskeletal agent; cytoskeleton-associated protein; microtubule; primary cilium

DOI:  https://doi.org/10.1002/jcp.30865
J Hypertens. 2022 Jun 01. 40(Suppl 1): e38

ENDOTHELIUM-SPECIFIC DEFICIENCY OF POLYCYSTIN-1 PROMOTES HYPERTENSION AND CARDIOVASCULAR DISORDERS.

Dominique Guerrot, Mouad Hamzaoui, Deborah Groussard, Dorian Nezam, Paul Mulder, Vincent Richard, Jeremy Bellien.

OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary kidney disease and is generally due to mutations in PKD1 and PKD2, encoding polycystins 1 and 2. In ADPKD, hypertension and cardiovascular (CV) disorders are highly prevalent but their mechanisms are partially understood. The objective of this study was to determine whether hypertension and the CV disorders of ADPKD are a consequence of the endothelial deficiency in the polycystin complex, rather than to the kidney disease, as is currently believed.
DESIGN AND METHOD: Since endothelial cells express the polycystin complex, where it plays a central role in the mechanotransduction of blood flow, we generated a murine model with inducible deletion of Pkd1 in endothelial cells (Cdh5-CreERT2;Pkd1fl/fl) to specifically determine the role of endothelial polycystin-1 in ADPKD. We nalysed the endothelial phenotype associated with Pkd1 deficiency, invasive and non-invasive blood pressure, vascular function on isolated vessels, and echocardiography. The impact on the development of a model of aorto-cava arterio-venous fistula and on the CV consequences of superimposed chronic kidney disease were nalysed to further establish the clinical relevance of our results.
RESULTS: As expected, transgenic mice presented normal kidney structure and function. Endothelial deletion of Pkd1 induced endothelial dysfunction, as demonstrated by impaired flow-mediated dilatation of resistance arteries and impaired relaxation to acetylcholine, increased blood pressure and prevented the normal development of arterio-venous fistula. In experimental chronic kidney disease induced by subtotal nephrectomy, endothelial deletion of Pkd1 further aggravated endothelial dysfunction, vascular remodelling and heart hypertrophy.
CONCLUSIONS: Altogether, this study provides the first in vivo demonstration that specific deletion of Pkd1 in endothelial cells promotes endothelial dysfunction and hypertension independently of kidney cysts and of impaired kidney function, impairs arterio-venous fistula development and potentiates the cardiovascular alterations associated with chronic kidney disease. It establishes the endothelium as a significant contributor to cardiovascular disease in ADPKD.

DOI: https://doi.org/10.1097/01.hjh.0000835596.33668.f9
Zhonghua Yi Xue Za Zhi. 2022 Aug 23. 102(31): 2441-2445

[Analysis of PKD1 gene mutation in a pedigree affected with autosomal dominant polycystic kidney disease].

D N Chen, G H Liu, Z N Zhu, F Xiong, B S Zhang.

Objective: To analyze the clinical phenotype and detect the pathogenic gene in a Chinese pedigree with autosomal dominant polycystic kidney disease(ADPKD). Methods: The proband of this study was hospitalized in Dongguan City People's Hospital on October 10, 2017, due to "left maxillary apical cyst". Clinical phenotypes were noted, imaging examinations and determination of biochemical indicators were carried out for the clinical diagnosis of the proband. Genomic DNA was extracted from peripheral venous blood. Whole-exome genotyping of the proband was performed with the next generation sequencing technology, and the candidate mutation site of the patient and his family members was verified by PCR and Sanger sequencing technology. The mutation site was further screened in 150 unrelated healthy Chinese controls. Mutation frequency within human populations and bioinformatics analysis were predicted with softwares including ExAC, dbSNP, HGMD, 1000 genomes, ClinVar, PKDB, Mutation Taster and PhyloP. Results: The proband, a 46-year-old male, was diagnosed with hypertension, positive urine occult blood and elevated blood creatinine. B-ultrasound and CT examinations showed that he had bilateral polycystic kidney with left kidney stones and polycystic liver. The gene analysis showed that the c.11017-10C>A heterozygous splice mutation in PKD1 gene was identified in the proband, his second younger brother, younger sister, daughter and niece, but absent in 150 healthy controls. Bioinformatics analysis showed it has been reported in the dbSNP, ClinVar, HGMD, PKDB and Mutation Taster databases. Some databases predicted it has a harmful function for probably leading to production of a truncated polycystin1(PC1) protein. Conclusion: c.11017-10C>A underlies the Chinese ADPKD pedigree and expands mutation spectrum of PKD1.

DOI: https://doi.org/10.3760/cma.j.cn112137-20220322-00610
J Hypertens. 2022 Jun 01. 40(Suppl 1): e249

IMPACT OF AQUAPORIN-3, AQUAPORIN-7 AND HEPARANASE GENETIC POLYMORPHISMS ON AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE PROGRESSION.

Ana Carolina Santos, Andreea Rechitean, Inês Vieira Da Silva, Andreia Matos, Joana Ferreira, Graça Soveral, Manuel Bicho, Edgar Almeida.

OBJECTIVE: Autosomal Dominant Polycystic Kidney Disease(ADPKD) is a monogenic disease characterized by the growth of cysts in the kidneys, which can progress to end-stage renal disease(ESRD). However, this progression is heterogeneous.Aquaporin-3(AQP3) and Aquaporin-7(AQP7) are water channels involved in the inflammatory response and proliferation, expressed in the kidney and may have a role in cyst epithelial proliferation. Heparanase(HPSE) is an enzyme that cleaves heparan sulfate side chains of proteoglycans and has an increased expression in the glomerulus in diseases associated with proteinuria.This study aims to evaluate the impact of AQP3, AQP7 and HPSE genetic polymorphisms and some biomarkers related to cardiovascular risk in ESRD progression in patients with ADPKD.
DESIGN AND METHOD: 95 ADPKD(52.6% females), mean age 44.78 ± 14.34 years were diagnosed and had follow-up> 60 months. Variation values of serum creatinine(SCr) were used to stratify patients into fast progressors(FP) and slow progressors. Biochemical parameters and genetic polymorphisms were determined by standardized methods and endpoint analysis, respectively. Statistical analysis was performed using SPSS software considering p-value < 0.05.
RESULTS: For HPSE, genotype AA was associated with increased risk for FP in CKD(p = 0.027), while allele G was associated with high values of SCr(p = 0.010). A trend was observed in genotype CC of AQP7 with higher SCr(p = 0.066). No associations were found between AQP3 polymorphism and progression in ADPKD.The increased levels of: creatinine(SCr), albumin creatinine ratio(Alb/Cr), microalbumin(mAlb) and parathyroid hormone(PTH) were associated with the FP and stage 4 and 5 of chronic kidney disease(CKD). The opposite occurred in hemoglobin(Hb) levels and the product of calcium and phosphorus. No associations were found between AQP3 polymorphism and progression in ADPKD.Higher values of SCr were found in genotype CC of AQP3(p = 0.016) and a trend in allele T of AQP7(p = 0.070) and genotype AA of HPSE(p = 0.056). PTH was higher in genotype CC of AQP3(p = 0.047).AQP7 polymorphism was associated with elevated values of:Alb/Scr(p = 0.021) in allele T, calcium(p = 0.003) in genotype TT and Hb(p = 0.012) in allele C.
CONCLUSIONS: The studied polymorphisms seem to directly impact and/or modulate levels of some biomarkers associated with progression and stage of CKD in ADPKD patients.

DOI: https://doi.org/10.1097/01.hjh.0000838040.47567.77
Clin Genet. 2022 Aug 27.

A Common Intronic Single Nucleotide Variant Modifies PKD1 Expression Level.

Zhengmao Zhang, Jon Blumenfeld, Andrew Ramnauth, Irina Barash, Pengbo Zhou, Daniel Levine, Thomas Parker, Hanna Rennert.

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 and PKD2 (PKD1/2), has unexplained phenotypic variability likely affected by environmental and other genetic factors. Approximately 10% of individuals with ADPKD phenotype have no causal mutation detected, possibly due to unrecognized risk variants of PKD1/2. This study was designed to identify risk variants of PKD genes through population genetic analyses. We used Wright's F-statistics (Fst) to evaluate common single nucleotide variants (SNVs) potentially favored by positive natural selection in PKD1 from 1000 Genomes Project (1KG) and genotyped 388 subjects from the Rogosin Institute ADPKD Data Repository. The variants with >90th percentile Fst scores underwent further investigation by in silico analysis and molecular genetics analyses. We identified a deep intronic SNV, rs3874648G>A, located in a conserved binding site of the splicing regulator Tra2-β in PKD1 intron 30. Reverse-transcription PCR (RT-PCR) of peripheral blood leukocytes (PBL) from an ADPKD patient homozygous for rs3874648-A identified an atypical PKD1 splice form. Functional analyses demonstrated that rs3874648-A allele increased Tra2-β binding affinity and activated a cryptic acceptor splice-site, causing a frameshift that introduced a premature stop codon in mRNA, thereby decreasing PKD1 full-length transcript level. PKD1 transcript levels were lower in PBL from rs3874648-G/A carriers than in rs3874648-G/G homozygotes in a small cohort of normal individuals and patients with PKD2 inactivating mutations. Our findings indicate that rs3874648G>A is a PKD1 expression modifier attenuating PKD1 expression through Tra2-β, while the derived G allele advantageously maintains PKD1 expression and is predominant in all subpopulations. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1111/cge.14214
Clin J Am Soc Nephrol. 2022 Aug 23. pii: CJN.04910422. [Epub ahead of print]

Drug Development for Cystic Kidney Diseases.

Sorin Fedeles, Ronald D Perrone.



Keywords:  clinical trial; drug development; polycystic kidney disease; regulatory development

DOI:  https://doi.org/10.2215/CJN.04910422
MicroPubl Biol. 2022 ;2022

The DYF-5 RCK and CDKL-1 CDKL5 kinases contribute differentially to shape distinct sensory neuron cilia morphologies in C. elegans.

Ashish Kumar Maurya, Piali Sengupta.

The conserved CCRK, RCK, and CDKL5 kinases regulate cilia length in diverse organisms. In C. elegans , DYF-18 CCRK regulates DYF-5 RCK to shape both simple and complex cilia morphologies. The CDKL5 ortholog CDKL-1 has also been suggested to act downstream of DYF-18 but independently of DYF-5 to regulate lengths of simple rod-like cilia. Here we show that CDKL-1 is largely dispensable for regulation of complex cilia structures. Using genetic epistasis experiments, we confirm that CDKL-1 and DYF-5 act independently to control cilia architecture. Our results indicate that multiple kinases act via distinct pathways to regulate unique cilia ultrastructures.

DOI: https://doi.org/10.17912/micropub.biology.000619
Elife. 2022 Aug 25. pii: e81016. [Epub ahead of print]11

GJA1 depletion causes ciliary defects by affecting Rab11 trafficking to the ciliary base.

Dong Gil Jang, Keun Yeong Kwon, Yeong Cheon Kweon, Byung-Gyu Kim, Kyungjae Myung, Hyun-Shik Lee, Chan Young Park, Taejoon Kwon, Tae Joo Park.

  The gap junction complex functions as a transport channel across the membrane. Among gap junction subunits, gap junction protein α1 (GJA1) is the most commonly expressed subunit. A recent study showed that GJA1 is necessary for the maintenance of motile cilia; however, the molecular mechanism and function of GJA1 in ciliogenesis remain unknown. Here, we examined the functions of GJA1 during ciliogenesis in human retinal pigment epithelium-1 and Xenopus laevis embryonic multiciliated-cells. GJA1 localizes to the motile ciliary axonemes or pericentriolar regions beneath the primary cilium. GJA1 depletion caused malformation of both the primary cilium and motile cilia. Further study revealed that GJA1 depletion affected several ciliary proteins such as BBS4, CP110, and Rab11 in the pericentriolar region and basal body. Interestingly, CP110 removal from the mother centriole was significantly reduced by GJA1 depletion. Importantly, Rab11, a key regulator during ciliogenesis, was immunoprecipitated with GJA1, and GJA1 knockdown caused the mislocalization of Rab11. These findings suggest that GJA1 regulates ciliogenesis by interacting with the Rab11-Rab8 ciliary trafficking pathway.

Keywords:  cell biology; developmental biology; mouse; xenopus

DOI:  https://doi.org/10.7554/eLife.81016