bims-bicyki 2022-05-29 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022‒05‒29
eighteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)

Regenerative Calcium Currents in Renal Primary Cilia.
Single Gene Mutations in Pkd1 or Tsc2 Alter Extracellular Vesicle Production and Trafficking.
Outcomes of Kidney Transplantation in Patients with Autosomal Dominant Polycystic Kidney Disease: Our Experience Based on 35-Years Follow-Up.
Deep Learning-Based Total Kidney Volume Segmentation in Autosomal Dominant Polycystic Kidney Disease Using Attention, Cosine Loss, and Sharpness Aware Minimization.
Establishment and Characterization of MUi027-A: A Novel Patient-Derived Cell Line of Polycystic Kidney Disease with PKD1 Mutation.
Rho-associated, coiled-coil-containing protein kinase 1 regulates development of diabetic kidney disease via modulation of fatty acid metabolism.
The interdependent relationship between the nitric oxide signaling pathway and primary cilia in pulse electromagnetic field-stimulated osteoblastic differentiation.
The predictive value of renal parenchymal information for renal function impairment in patients with ADPKD: a multicenter prospective study.
Complex Presentation of Hao-Fountain Syndrome Solved by Exome Sequencing Highlighting Co-Occurring Genomic Variants.
Change in Urinary Myoinositol/Citrate Ratio Associates with Progressive Loss of Renal Function in ADPKD Patients.
The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.
A Spontaneous Extracranial Internal Carotid Artery Dissection with Autosomal Dominant Polycystic Kidney Disease: A Case Report and Literature Review.
Loss of Polycystin-1 causes cAMP-dependent switch from tubule to cyst formation.
BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to IFT turnaround involving ICK/CILK1.
Crosstalk between cilia and autophagy: implication for human diseases.
Recessive PKD1 Mutations Are Associated With Febrile Seizures and Epilepsy With Antecedent Febrile Seizures and the Genotype-Phenotype Correlation.
Inhaled delivery of a lipid nanoparticle encapsulated messenger RNA encoding a ciliary protein for the treatment of primary ciliary dyskinesia.
High Nasal Nitric Oxide, Cilia Analyses and Genotypes in a Retrospective Cohort of Children with Primary Ciliary Dyskinesia.

Front Physiol. 2022 ;13 894518

Regenerative Calcium Currents in Renal Primary Cilia.

Steven J Kleene.

  Polycystic kidney disease (PKD) is a leading cause of end-stage renal disease. PKD arises from mutations in proteins, one a Ca2+-conducting channel, expressed in the primary cilia of renal epithelial cells. A common hypothesis is that Ca2+ entering through ciliary ion channels may reduce cystogenesis. The cilia have at least two Ca2+-conducting channels: polycystin-2 (PC2) and TRPV4 (transient receptor potential (TRP) cation channel, subfamily V, member 4), but how substantially they can increase intraciliary Ca2+ is unknown. By recording channel activities in isolated cilia, conditions are identified under which the channels can increase free Ca2+ within the cilium by at least 500-fold through regenerative (positive-feedback) signaling. Ca2+ that has entered through a channel can activate the channel internally, which increases the Ca2+ influx, and so on. Regenerative signaling is favored when the concentration of the Ca2+ buffer is reduced or when a slower buffer is used. Under such conditions, the Ca2+ that enters the cilium through a single PC2 channel is sufficient to almost fully activate that same channel. Regenerative signaling is not detectable with reduced external Ca2+. Reduced buffering also allows regenerative signaling through TRPV4 channels, but not through TRPM4 (TRP subfamily M, member 4) channels, which are activated by Ca2+ but do not conduct it. On a larger scale, Ca2+ that enters through TRPV4 channels can cause secondary activation of PC2 channels. I discuss the likelihood of regenerative ciliary Ca2+ signaling in vivo, a possible mechanism for its activation, and how it might relate to cystogenesis.

Keywords:  PC2; TRPV4; calcium signaling; polycystic kidney disease; polycystin-2; primary cilium

DOI:  https://doi.org/10.3389/fphys.2022.894518
Biology (Basel). 2022 May 06. pii: 709. [Epub ahead of print]11(5):

Single Gene Mutations in Pkd1 or Tsc2 Alter Extracellular Vesicle Production and Trafficking.

Prashant Kumar, Fahad Zadjali, Ying Yao, Michael Köttgen, Alexis Hofherr, Kenneth W Gross, Darshan Mehta, John J Bissler.

  Patients with autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex (TSC) are born with normal or near-normal kidneys that later develop cysts and prematurely lose function. Both renal cystic diseases appear to be mediated, at least in part, by disease-promoting extracellular vesicles (EVs) that induce genetically intact cells to participate in the renal disease process. We used centrifugation and size exclusion chromatography to isolate the EVs for study. We characterized the EVs using tunable resistive pulse sensing, dynamic light scattering, transmission electron microscopy, and Western blot analysis. We performed EV trafficking studies using a dye approach in both tissue culture and in vivo studies. We have previously reported that loss of the Tsc2 gene significantly increased EV production and here demonstrate that the loss of the Pkd1 gene also significantly increases EV production. Using a cell culture system, we also show that loss of either the Tsc2 or Pkd1 gene results in EVs that exhibit an enhanced uptake by renal epithelial cells and a prolonged half-life. Loss of the primary cilia significantly reduces EV production in renal collecting duct cells. Cells that have a disrupted Pkd1 gene produce EVs that have altered kinetics and a prolonged half-life, possibly impacting the duration of the EV cargo effect on the recipient cell. These results demonstrate the interplay between primary cilia and EVs and support a role for EVs in polycystic kidney disease pathogenesis.

Keywords:  autosomal dominant polycystic kidney disease (ADPKD); cystogenesis; extracellular vesicles (EVs); primary cilia; renal cyst; tuberous sclerosis complex (TSC)

DOI:  https://doi.org/10.3390/biology11050709
Diagnostics (Basel). 2022 May 08. pii: 1174. [Epub ahead of print]12(5):

Outcomes of Kidney Transplantation in Patients with Autosomal Dominant Polycystic Kidney Disease: Our Experience Based on 35-Years Follow-Up.

Tsung-Yin Tsai, Cheng-Hsu Chen, Ming-Ju Wu, Shang-Feng Tsai.

  BACKGROUND AND OBJECTIVES: For patients with end-stage renal disease (ESRD), the best replacement therapy is renal transplant (RTx) to ensure life with good quality. Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder and a common cause of ESRD. Different from ESRD of other causes, ADPKD patients need careful pre-RTx evaluations like detecting the presence of intracranial aneurisms, cardiac manifestations, and complications of liver and renal cysts.MATERIALS: We retrieved a total of 1327 RTx patients receiving 1382 times RTx (two recipients with three times, 48 recipients with two times) over the last 35 years. Only 41 of these patients were diagnosed with ADPKD.
RESULTS: At the first RTx, patients' ages were 42.9 ± 12.6 (mean ± SD) years. Ages of the ADPKD group (52.5 ± 10.1 years) were older than the non-ADPKD group (42.7 ± 12.7 years, p = 0.001). We found more cell mediated and antibody mediated rejection (29.3% vs. 26.0%, and 22.0% vs. 7.0%; both p < 0.001), new onset diabetes after transplant (NODAT) (21, 51.2% vs. 326, 25.3%; p = 0.005), and worse graft survival (p < 0.001) in the ADPKD group, and with the development of more malignancies (18; 43.9% vs. 360; 28.0%; p = 0.041). The long-term patient survivals were poorer in the ADPKD group (38.9% vs. 70.3%; p = 0.018). ADPKD was found as an independent risk factor for long-term patient survival (HR = 2.64, 95% CI 1.03-6.76, p = 0.04).
CONCLUSIONS: Patients with ADPKD-related ESRD developed more NODAT, and also more malignancies if not aggressively surveyed before surgery. Due to poor long-term graft and patient survivals, regular careful examinations for NODAT and malignancies, even in the absence of related symptoms and signs, are highly recommended in the follow-ups.

Keywords:  autosomal dominant polycystic kidney disease; malignancy; new onset diabetes mellitus after transplantation; patient survival; renal transplantation

DOI:  https://doi.org/10.3390/diagnostics12051174
Diagnostics (Basel). 2022 May 07. pii: 1159. [Epub ahead of print]12(5):

Deep Learning-Based Total Kidney Volume Segmentation in Autosomal Dominant Polycystic Kidney Disease Using Attention, Cosine Loss, and Sharpness Aware Minimization.

Anish Raj, Fabian Tollens, Laura Hansen, Alena-Kathrin Golla, Lothar R Schad, Dominik Nörenberg, Frank G Zöllner.

  Early detection of the autosomal dominant polycystic kidney disease (ADPKD) is crucial as it is one of the most common causes of end-stage renal disease (ESRD) and kidney failure. The total kidney volume (TKV) can be used as a biomarker to quantify disease progression. The TKV calculation requires accurate delineation of kidney volumes, which is usually performed manually by an expert physician. However, this is time-consuming and automated segmentation is warranted. Furthermore, the scarcity of large annotated datasets hinders the development of deep learning solutions. In this work, we address this problem by implementing three attention mechanisms into the U-Net to improve TKV estimation. Additionally, we implement a cosine loss function that works well on image classification tasks with small datasets. Lastly, we apply a technique called sharpness aware minimization (SAM) that helps improve the generalizability of networks. Our results show significant improvements (p-value < 0.05) over the reference kidney segmentation U-Net. We show that the attention mechanisms and/or the cosine loss with SAM can achieve a dice score (DSC) of 0.918, a mean symmetric surface distance (MSSD) of 1.20 mm with the mean TKV difference of -1.72%, and R2 of 0.96 while using only 100 MRI datasets for training and testing. Furthermore, we tested four ensembles and obtained improvements over the best individual network, achieving a DSC and MSSD of 0.922 and 1.09 mm, respectively.

Keywords:  attention; autosomal dominant polycystic kidney disease; cosine loss; deep learning; image segmentation; magnetic resonance imaging; sharpness aware minimization; total kidney volume

DOI:  https://doi.org/10.3390/diagnostics12051159
J Pers Med. 2022 May 09. pii: 766. [Epub ahead of print]12(5):

Establishment and Characterization of MUi027-A: A Novel Patient-Derived Cell Line of Polycystic Kidney Disease with PKD1 Mutation.

Aung Khine Linn, Warun Maneepitasut, Alisa Tubsuwan, Narisorn Kitiyanant, Bunyong Phakdeekitcharoen, Suparerk Borwornpinyo, Suradej Hongeng, Phetcharat Phanthong.

  Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent genetic diseases affecting the kidneys. A genetically specific mutation model is required to comprehend its pathophysiology and to develop a drug treatment. In this study, we successfully developed human induced pluripotent stem cells (hiPSCs) named MUi027-A from skin fibroblasts of a patient diagnosed with ADPKD and carrying the PKD1 frameshift mutation (c.7946_7947delCT). MUi027-A cells showed the same genetic fingerprints as the parental cells, including the presence of the PKD1 mutation. MUi027-A hiPSCs displayed embryonic stem cell-like characteristics with the capability of differentiating into the three germ layers. Upon directed differentiation, MUi027-A hiPSCs could be differentiated into tubular organoids with the expression of renal cell markers. Furthermore, we compared the efficiency of cyst formation in two human iPSC lines with different PKD1 mutations. When cyst formation was induced by either forskolin or blebbistatin, MUi027-A hiPSC-derived kidney organoids displayed higher frequencies of cyst formation when compared to organoids generated from an iPSC cell line with non-truncating PKD1 mutation genotype (c.5878C > T), suggesting the presence of physiological differences in the mechanism of cyst formation between different PKD1 mutants. Overall, we generated and characterized a novel human iPSC line with a specific PKD mutation and demonstrated its potential as a disease model to study the pathophysiology of genetic determinants in the development of ADPKD disease.

Keywords:  PKD; autosomal dominant polycystic kidney disease; disease model; episomal reprogramming; human induced pluripotent stem cells; patient-derived cell line

DOI:  https://doi.org/10.3390/jpm12050766
Kidney Int. 2022 May 18. pii: S0085-2538(22)00370-2. [Epub ahead of print]

Rho-associated, coiled-coil-containing protein kinase 1 regulates development of diabetic kidney disease via modulation of fatty acid metabolism.

Yosuke Nagai, Keiichiro Matoba, Yusuke Takeda, Hideji Yako, Tomoyo Akamine, Kensuke Sekiguchi, Yasushi Kanazawa, Tamotsu Yokota, Kazunori Sango, Daiji Kawanami, Kazunori Utsunomiya, Rimei Nishimura.

  Dysregulation of fatty acid utilization is increasingly recognized as a significant component of diabetic kidney disease. Rho-associated, coiled-coil-containing protein kinase (ROCK) is activated in the diabetic kidney, and studies over the past decade have illuminated ROCK signaling as an essential pathway in diabetic kidney disease. Here, we confirmed the distinct role of ROCK1, an isoform of ROCK, in fatty acid metabolism using glomerular mesangial cells and ROCK1 knockout mice. Mesangial cells with ROCK1 deletion were protected from mitochondrial dysfunction and redox imbalance driven by transforming growth factor β, a cytokine upregulated in diabetic glomeruli. We found that high-fat diet-induced obese ROCK1 knockout mice exhibited reduced albuminuria and histological abnormalities along with the recovery of impaired fatty acid utilization and mitochondrial fragmentation. Mechanistically, we found that ROCK1 regulates the induction of critical mediators in fatty acid metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1α, carnitine palmitoyltransferase 1, and widespread program-associated cellular metabolism. Thus, our findings highlight ROCK1 as an important regulator of energy homeostasis in mesangial cells in the overall pathogenesis of diabetic kidney disease.

Keywords:  AMP-activated protein kinase; ROCK1; Rho-kinase; diabesity-related kidney disease; fatty acid oxidation

DOI:  https://doi.org/10.1016/j.kint.2022.04.021
FASEB J. 2022 Jun;36(6): e22376

The interdependent relationship between the nitric oxide signaling pathway and primary cilia in pulse electromagnetic field-stimulated osteoblastic differentiation.

Wen-Fang He, Rong Qin, Yu-Hai Gao, Jian Zhou, Juan-Juan Wei, Jing Liu, Xue-Feng Hou, Hui-Ping Ma, Cory J Xian, Xue-Yan Li, Ke-Ming Chen.

  Pulsed electromagnetic fields (PEMFs) have long been recognized being safe and effective in treating bone fracture nonunion and osteoporosis. However, the mechanism of osteogenic action of PEMFs is still unclear. While primary cilia are reported to be a sensory organelle for PEMFs, and nitric oxide (NO) plays an indispensable role in osteogenic effect of PEMFs, the relationship between NO and primary cilia is unknown. In this study, effects of treatment with 50 Hz 0.6 mT PEMFs on osteogenic differentiation and mineralization, NO secretion, and ciliary location of specific proteins were examined in rat calvarial osteoblasts (ROBs) with normal or abrogated primary cilia. It was found that PEMFs stimulated the osteogenic differentiation by activating the NOS/NO/sGC/cGMP/PKG signaling pathway, which need the existence of primary cilia. All components of the signaling pathway including iNOS, eNOS, sGC, PKG-1, and PKG-2 were localized to primary cilia, and eNOS was phosphorylated inside the primary cilia. Besides, primary cilia were elongated significantly by PEMF treatment and changed dynamically with the activation NO/cGMP pathway. When the pathway was blocked by L-NAME, PEMFs could no longer elongate the primary cilia and stimulate the osteoblastic differentiation. Thus, this study for the first time observed activation of the NO/cGMP signaling pathway in ciliary compartment of osteoblasts, and PEMFs could not stimulate the osteoblastic differentiation if the NO signaling pathway was blocked or the ciliogenesis was inhibited. Our findings indicate the interdependent relationship between NO and primary cilia in the PEMF-promoted osteogenesis.

Keywords:  endothelial nitric oxide synthase; nitric oxide; osteogenic differentiation; primary cilia; pulsed electromagnetic fields

DOI:  https://doi.org/10.1096/fj.202101577RR
Abdom Radiol (NY). 2022 May 28.

The predictive value of renal parenchymal information for renal function impairment in patients with ADPKD: a multicenter prospective study.

Yuhang Xie, Mengmiao Xu, Yajie Chen, Xiaolan Zhu, Shenghong Ju, Yuefeng Li.

  OBJECTIVE: Although the guideline indicates that total kidney volume (TKV) is an important detection indicator in patients with autosomal dominant polycystic kidney disease (ADPKD), this study attempted to demonstrate that renal parenchymal information, combined with parenchymal volume and radiomics features, may have more valuable clinical guiding significance.METHODS: A totals of 340 ADPKD patients with normal renal function were prospectively collected and followed-up for five years, with renal function tests and non-contrast computed tomography (CT) performed every six months. The relationship between renal function impairment and renal parenchymal volume (RPV) as along with radiomics features was explored using a multiple linear regression model and multiple logistic regression. Then, a combined model of RPV with radiomics features was constructed to comprehensively evaluate its predictive value.
RESULTS: Compared with TKV, decreased RPV presented a closer relationship with renal function impairment, namely, with the impairment rate (RPV: 82.3% vs. TVK: 67.1%) and eGFR (RPV: r = 0.614, p < 0.001 vs. TKV: r = -0.452, p < 0.001), and showed higher predictive power (RPV: AUC = 0.752 [95%CI 0.692-0.805], p < 0.001 vs. TKV: AUC = 0.711 [95%CI 0.649-0.768], p < 0.001). Correspondingly, the radiomics analysis that was derived from the renal parenchyma also showed a satisfactory result (AUC = 0.849 [95%Cl 0.797-0.892], p < 0.001). Importantly, the predictive power for renal function impairment was further improved in the combined model of RPV and radiomics features (AUC = 0.902 [95%Cl 0.857-0.937], p < 0.001).
CONCLUSION: Renal parenchyma information may be a sensitive biomarker of renal function impairment in ADPKD, which can provide a new approach for clinically monitoring renal function, and may greatly improve the pre-hospital prevention and treatment effects.

Keywords:  Non-contrast computed tomography; Polycystic kidney disease; Radiomics analysis; Renal function impairment; Renal parenchymal volume

DOI:  https://doi.org/10.1007/s00261-022-03554-w
Genes (Basel). 2022 May 16. pii: 889. [Epub ahead of print]13(5):

Complex Presentation of Hao-Fountain Syndrome Solved by Exome Sequencing Highlighting Co-Occurring Genomic Variants.

Manuela Priolo, Cecilia Mancini, Simone Pizzi, Luigi Chiriatti, Francesca Clementina Radio, Viviana Cordeddu, Letizia Pintomalli, Corrado Mammì, Bruno Dallapiccola, Marco Tartaglia.

  OBJECTIVE: The co-occurrence of pathogenic variants has emerged as a relatively common finding underlying complex phenotypes. Here, we used whole-exome sequencing (WES) to solve an unclassified multisystem clinical presentation.PATIENTS AND METHODS: A 20-year-old woman affected by moderate intellectual disability (ID), dysmorphic features, hypertrichosis, scoliosis, recurrent bronchitis, and pneumonia with bronchiectasis, colelithiasis, chronic severe constipation, and a family history suggestive of autosomal dominant recurrence of polycystic kidney disease was analyzed by WES to identify the genomic events underlying the condition.
RESULTS: Four co-occurring genomic events fully explaining the proband's clinical features were identified. A de novo truncating USP7 variant was disclosed as the cause of Hao-Fountain syndrome, a disorder characterized by syndromic ID and distinctive behavior. Compound heterozygosity for a major cystic fibrosis-causing variant and the modulator allele, IVS8-5T, in CFTR explained the recurrent upper and lower respiratory way infections, bronchiectasis, cholelithiasis, and chronic constipation. Finally, a truncating PKD2 variant co-segregating with polycystic kidney disease in the family allowed presymptomatic disease diagnosis.
CONCLUSIONS: The co-occurring variants in USP7 and CFTR variants explained the multisystem disorder of the patient. The comprehensive dissection of the phenotype and early diagnosis of autosomal dominant polycystic kidney disease allowed us to manage the CFTR-related disorder symptoms and monitor renal function and other complications associated with PKD2 haploinsufficiency, addressing proper care and surveillance.

Keywords:  CFTR; HAFOUS; PKD2; USP7; WES; cystic fibrosis; dual molecular diagnosis

DOI:  https://doi.org/10.3390/genes13050889
Am J Nephrol. 2022 May 25. 1-11

Change in Urinary Myoinositol/Citrate Ratio Associates with Progressive Loss of Renal Function in ADPKD Patients.

DIPAK Consortium

  INTRODUCTION: In autosomal dominant polycystic kidney disease (ADPKD) patients, predicting renal disease progression is important to make a prognosis and to support the clinical decision whether to initiate renoprotective therapy. Conventional markers all have their limitations. Metabolic profiling is a promising strategy for risk stratification. We determined the prognostic performance to identify patients with a fast progressive disease course and evaluated time-dependent changes in urinary metabolites.METHODS: Targeted, quantitative metabolomics analysis (1H NMR-spectroscopy) was performed on spot urinary samples at two time points, baseline (n = 324, 61% female; mean age 45 years, SD 11; median eGFR 61 mL/min/1.73 m2, IQR 42-88; mean years of creatinine follow-up 3.7, SD 1.3) and a sample obtained after 3 years of follow-up (n = 112). Patients were stratified by their eGFR slope into fast and slow progressors based on an annualized change of > -3.0 or ≤ -3.0 mL/min/1.73 m2/year, respectively. Fifty-five urinary metabolites and ratios were quantified, and the significant ones were selected. Logistic regression was used to determine prognostic performance in identifying those with a fast progressive course using baseline urine samples. Repeated-measures ANOVA was used to analyze whether changes in urinary metabolites over a 3-year follow-up period differed between fast and slow progressors.
RESULTS: In a single urinary sample, the prognostic performance of urinary metabolites was comparable to that of a model including height-adjusted total kidney volume (htTKV, AUC = 0.67). Combined with htTKV, the predictive value of the metabolite model increased (AUC = 0.75). Longitudinal analyses showed an increase in the myoinositol/citrate ratio (p < 0.001) in fast progressors, while no significant change was found in those with slow progression, which is in-line with an overall increase in the myoinositol/citrate ratio as GFR declines.
CONCLUSION: A metabolic profile, measured at a single time point, showed at least equivalent prognostic performance to an imaging-based risk marker in ADPKD. Changes in urinary metabolites over a 3-year follow-up period were associated with a fast progressive disease course.

Keywords:  Autosomal dominant polycystic kidney disease; Biomarker; Estimated glomerular filtration rate slope; Progression; Urine metabolites

DOI:  https://doi.org/10.1159/000524851
Mol Biol Cell. 2022 Jun 01. 33(7): cor1

The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic.

Rachel E Turn, Yihan Hu, Skylar I Dewees, Narra Devi, Michael P East, Katherine R Hardin, Tala Khatib, Joshua Linnert, Uwe Wolfrum, Michael J Lim, James E Casanova, Tamara Caspary, Richard A Kahn.

DOI: https://doi.org/10.1091/mbc.E21-09-0443_corr
Medicina (Kaunas). 2022 May 20. pii: 679. [Epub ahead of print]58(5):

A Spontaneous Extracranial Internal Carotid Artery Dissection with Autosomal Dominant Polycystic Kidney Disease: A Case Report and Literature Review.

Tsuyoshi Izumo, Yuka Ogawa, Ayaka Matsuo, Kazuaki Okamura, Ryotaro Takahira, Eisaku Sadakata, Michiharu Yoshida, Susumu Yamaguchi, Yohei Tateishi, Shiro Baba, Yoichi Morofuji, Takeshi Hiu, Takeo Anda, Takayuki Matsuo.

  Background and Objectives: Non-cystic manifestation of autosomal dominant polycystic kidney disease (ADPKD) is an important risk factor for cerebral aneurysms. In this report, we describe a rare spontaneous internal carotid artery (ICA) dissection in a patient with ADPKD. Observations: A 38-year-old woman with a history of ADPKD and acute myocardial infarction due to coronary artery dissection experienced severe spontaneous pain on the left side of her neck. Magnetic resonance imaging (MRI) revealed a severe left ICA stenosis localized at its origin. Carotid plaque MRI showed that the stenotic lesion was due to a subacute intramural hematoma. Close follow-up by an imaging study was performed under the diagnosis of spontaneous extracranial ICA dissection, and spontaneous regression of the intramural hematoma was observed uneventfully. Conclusions: When patients with a history of ADPKD present with severe neck pain, it is crucial to consider the possibility of a spontaneous ICA dissection. A carotid plaque MRI is beneficial in the differential diagnosis. Conservative management may benefit patients without ischemic symptoms.

Keywords:  ADPKD; ICA dissection; plaque imaging

DOI:  https://doi.org/10.3390/medicina58050679
iScience. 2022 Jun 17. 25(6): 104359

Loss of Polycystin-1 causes cAMP-dependent switch from tubule to cyst formation.

Julia Katharina Scholz, Andre Kraus, Dominik Lüder, Kathrin Skoczynski, Mario Schiffer, Steffen Grampp, Johannes Schödel, Bjoern Buchholz.

  Autosomal dominant polycystic kidney disease is the most common monogenic disease that causes end-stage renal failure. It primarily results from mutations in the PKD1 gene that encodes for Polycystin-1. How loss of Polycystin-1 translates into bilateral renal cyst development is mostly unknown. cAMP is significantly involved in cyst enlargement but its role in cyst initiation has remained elusive. Deletion of Polycystin-1 in collecting duct cells resulted in a switch from tubule to cyst formation and was accompanied by an increase in cAMP. Pharmacological elevation of cAMP in Polycystin-1-competent cells caused cyst formation, impaired plasticity, nondirectional migration, and mis-orientation, and thus strongly resembled the phenotype of Polycystin-1-deficient cells. Mis-orientation of developing tubule cells in metanephric kidneys upon loss of Polycystin-1 was phenocopied by pharmacological increase of cAMP in wildtype kidneys. In vitro, cAMP impaired tubule formation after capillary-induced injury which was further impaired by loss Polycystin-1.

Keywords:  machine learning; nephrology

DOI:  https://doi.org/10.1016/j.isci.2022.104359
Mol Biol Cell. 2022 May 24. mbcE22030089

BROMI/TBC1D32 together with CCRK/CDK20 and FAM149B1/JBTS36 contributes to IFT turnaround involving ICK/CILK1.

Yuuki Satoda, Tatsuro Noguchi, Taiju Fujii, Aoi Taniguchi, Yohei Katoh, Kazuhisa Nakayama.

Primary cilia are antenna-like organelles that contain specific proteins, and are crucial for tissue morphogenesis. Anterograde and retrograde trafficking of ciliary proteins are mediated by the intraflagellar transport (IFT) machinery. BROMI/TBC1D32 interacts with CCRK/CDK20, which phosphorylates and activates the ICK/CILK1 kinase, to regulate the change in direction of the IFT machinery at the ciliary tip. Mutations in BROMI, CCRK, and ICK in humans cause ciliopathies, and mice defective in these genes are also known to demonstrate ciliopathy phenotypes. We here show that BROMI interacts not only with CCRK but also with CFAP20, an evolutionarily conserved ciliary protein, and with FAM149B1/JBTS36, a protein in which mutations cause Joubert syndrome. In addition, we show that FAM149B1 interacts directly with CCRK as well as with BROMI. Ciliary defects observed in CCRK-knockout (KO), BROMI-KO, and FAM149B1-KO cells, including abnormally long cilia and accumulation of the IFT machinery and ICK at the ciliary tip, resembled one another, and BROMI mutants that are defective in binding to CCRK and CFAP20 were unable to rescue the ciliary defects of BROMI-KO cells. These data indicate that CCRK, BROMI, FAM149B1, and probably CFAP20, all together regulate the IFT turnaround process under the control of ICK. [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E22-03-0089
Autophagy. 2022 May 25. 1-20

Crosstalk between cilia and autophagy: implication for human diseases.

Manuela Morleo, Helena L A Vieira, Petra Pennekamp, Alessandro Palma, Liliana Bento-Lopes, Heymut Omran, Susana S Lopes, Duarte C Barral, Brunella Franco.

  Macroautophagy/autophagy is a self-degradative process necessary for cells to maintain their energy balance during development and in response to nutrient deprivation. Autophagic processes are tightly regulated and have been found to be dysfunctional in several pathologies. Increasing experimental evidence points to the existence of an interplay between autophagy and cilia. Cilia are microtubule-based organelles protruding from the cell surface of mammalian cells that perform a variety of motile and sensory functions and, when dysfunctional, result in disorders known as ciliopathies. Indeed, selective autophagic degradation of ciliary proteins has been shown to control ciliogenesis and, conversely, cilia have been reported to control autophagy. Moreover, a growing number of players such as lysosomal and mitochondrial proteins are emerging as actors of the cilia-autophagy interplay. However, some of the published data on the cilia-autophagy axis are contradictory and indicate that we are just starting to understand the underlying molecular mechanisms. In this review, the current knowledge about this axis and challenges are discussed, as well as the implication for ciliopathies and autophagy-associated disorders.

Keywords:  Autophagy; cilia; human diseases; lysosome; macroautophagy; mitochondria

DOI:  https://doi.org/10.1080/15548627.2022.2067383
Front Mol Neurosci. 2022 ;15 861159

Recessive PKD1 Mutations Are Associated With Febrile Seizures and Epilepsy With Antecedent Febrile Seizures and the Genotype-Phenotype Correlation.

Jing-Yang Wang, Jie Wang, Xin-Guo Lu, Wang Song, Sheng Luo, Dong-Fang Zou, Li-Dong Hua, Qian Peng, Yang Tian, Liang-Di Gao, Wei-Ping Liao, Na He.

  Objective: The PKD1 encodes polycystin-1, a large transmembrane protein that plays important roles in cell proliferation, apoptosis, and cation transport. Previous studies have identified PKD1 mutations in autosomal dominant polycystic kidney disease (ADPKD). However, the expression of PKD1 in the brain is much higher than that in the kidney. This study aimed to explore the association between PKD1 and epilepsy.Methods: Trios-based whole-exome sequencing was performed in a cohort of 314 patients with febrile seizures or epilepsy with antecedent febrile seizures. The damaging effects of variants was predicted by protein modeling and multiple in silico tools. The genotype-phenotype association of PKD1 mutations was systematically reviewed and analyzed.
Results: Eight pairs of compound heterozygous missense variants in PKD1 were identified in eight unrelated patients. All patients suffered from febrile seizures or epilepsy with antecedent febrile seizures with favorable prognosis. All of the 16 heterozygous variants presented no or low allele frequencies in the gnomAD database, and presented statistically higher frequency in the case-cohort than that in controls. These missense variants were predicted to be damaging and/or affect hydrogen bonding or free energy stability of amino acids. Five patients showed generalized tonic-clonic seizures (GTCS), who all had one of the paired missense mutations located in the PKD repeat domain, suggesting that mutations in the PKD domains were possibly associated with GTCS. Further analysis demonstrated that monoallelic mutations with haploinsufficiency of PKD1 potentially caused kidney disease, compound heterozygotes with superimposed effects of two missense mutations were associated with epilepsy, whereas the homozygotes with complete loss of PKD1 would be embryonically lethal.
Conclusion: PKD1 gene was potentially a novel causative gene of epilepsy. The genotype-phenotype relationship of PKD1 mutations suggested a quantitative correlation between genetic impairment and phenotypic variation, which will facilitate the genetic diagnosis and management in patients with PKD1 mutations.

Keywords:  PKD1 gene; compound heterozygous mutations; epilepsy with antecedent febrile seizures; genotype-phenotype association; monoallelic mutation

DOI:  https://doi.org/10.3389/fnmol.2022.861159
Pulm Pharmacol Ther. 2022 May 22. pii: S1094-5539(22)00025-6. [Epub ahead of print] 102134

Inhaled delivery of a lipid nanoparticle encapsulated messenger RNA encoding a ciliary protein for the treatment of primary ciliary dyskinesia.

Caroline J Woo, Ayed Allawzi, Nicholas Clark, Neha Kaushal, Tim Efthymiou, Maike Thamsen, Jane Ngyuen, Richard Wooster, James Sullivan.

  Primary ciliary dyskinesia (PCD) is a respiratory disease caused by dysfunction of the cilia with currently no approved treatments. This predominantly autosomal recessive disease is caused by mutations in any one of over 50 genes involved in cilia function; DNAI1 is one of the more frequently mutated genes, accounting for approximately 5-10% of diagnosed PCD cases. A codon-optimized mRNA encoding DNAI1 and encapsulated in a lipid nanoparticle (LNP) was administered to mice via aerosolized inhalation resulting in the expression human DNAI1 in the multiciliated cells of the pseudostratified columnar epithelia. The spatial localization of DNAI1 expression in the bronchioles indicate that delivery of the DNAI1 mRNA transpires the lower airways. In a PCD disease model, exposure to the LNP-encapsulated DNAI1 mRNA resulted in increased ciliary beat frequency using high speed videomicroscopy showing the potential for an mRNA therapeutic to correct cilia function in patients with PCD due to DNAI1 mutations.

Keywords:  Dynein axonemal intermediate chain 1; Inhaled; Lipid nanoparticle; Messenger RNA; Primary ciliary dyskinesia

DOI:  https://doi.org/10.1016/j.pupt.2022.102134
Ann Am Thorac Soc. 2022 May 27.

High Nasal Nitric Oxide, Cilia Analyses and Genotypes in a Retrospective Cohort of Children with Primary Ciliary Dyskinesia.

Marie Legendre, Guillaume Thouvenin, Jessica Taytard, Marguerite Baron, Muriel Le Bourgeois, Aline Tamalet, Rahma Mani, Gregory Jouvion, Serge Amselem, Estelle Escudier, Nicole Beydon.

RATIONALE: While children with primary ciliary dyskinesia (PCD) typically have low nasal nitric oxide (nNO), some children with indisputable PCD may have unexplained high nNO levels.OBJECTIVES: To look for relationships between nNO measures and genetic findings (and cilia motility or ultrastructure when available) in PCD children with a known genotype.
METHODS: We studied retrospectively 73 PCD children (median (range) age 9.5 (2.1 to 18.2) years). nNO was the mean value of a plateau reached while velum was closed (nNO-VC, threshold 77 nL.min-1), or calculated as the average of 5 peaks obtained during tidal breathing (nNO-TB, threshold 40 nL.min-1). Cilia beat was classified either as motile (including dyskinetic pattern) or immotile depending on whether motility was present or absent in all cilia, or as a mixture of motile and immotile cilia. Genotypes were classified as: pathogenic mutations in a gene known to be associated with high nNO (mild genotype); bi-allelic truncating mutations in other genes (severe mutations); putative hypomorphic pathogenic mutation (missense, single amino-acid deletion or moderate splicing mutations) in at least one allele thought to be possibly associated with a residual production of a functional protein.
RESULTS: nNO was above the discriminant threshold in 16/73 (21.9%) children (11 nNO-VC and 5 nNO-TB). High nNO was less frequent in children with severe mutations (2/42) than in those with mild genotypes (7/10) or at least one hypomorphic mutation (7/21)(P < 0.0001). Median [IQR] nNO-VC values (n=60) were significantly different in the three genotypic groups: severe mutations 18 [10;26] nL.min-1 (n=36), possible residual functional protein production (putative hypomorphic mutations) 23 [16;68] nL.min-1 (n=17), and mild genotypes 139 [57;216] nL.min-1 (n=7); P=0.0002. The higher the cilia motility the higher the nNO-VC (16 [10;23], 23 [17;56], and 78 [45;93] nL.min-1 in patients with respectively immotile, dyskinetic motile/immotile, and dyskinetic motile cilia; P<0.0001), while nNO values were scattered across different ultrastructure defects (P = 0.07).
CONCLUSIONS: In PCD children, high nNO values were linked not only to specific genes and but also to potentially hypomorphic mutations in other genes (with possible functional protein production). nNO values increased with the proportion of motile cilia.

DOI: https://doi.org/10.1513/AnnalsATS.202110-1175OC