bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022–10–23
fourteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Polycystin-2 (TRPP2) regulates primary cilium length in LLC-PK1 renal epithelial cells.
  2. XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice.
  3. Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.
  4. Synergistic effect of anticancer drug resistance and Wnt3a on primary ciliogenesis in A549 cell-derived anticancer drug-resistant subcell lines.
  5. A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease.
  6. Real clinical experience after one year of treatment with tolvaptan in patients with autosomal dominant polycystic kidney disease.
  7. LRRK1-mediated NDEL1 phosphorylation promotes cilia disassembly via dynein-2-driven retrograde intraflagellar transport.
  8. Disease-associated mutations in WDR34 lead to diverse impacts on the assembly and function of dynein-2.
  9. Novel aspects of intra-islet communication: Primary cilia and filopodia.
  10. Arl13b controls basal cell stemness properties and Hedgehog signaling in the mouse epididymis.
  11. ATM- and ATR-induced primary ciliogenesis promotes cisplatin resistance in pancreatic ductal adenocarcinoma.
  12. CFAP300 mutation causing primary ciliary dyskinesia in Finland.
  13. Fasudil, a ROCK inhibitor, prevents neuropathic pain in Minamata disease model rats.
  14. Having Multiple Renal Cysts in a Young Adult is not Always a Sign of Polycystic Kidney Disease.
  1. Front Physiol. 2022 ;13 995473
    Polycystin-2 (TRPP2) regulates primary cilium length in LLC-PK1 renal epithelial cells.
    Noelia Scarinci, Paula L Perez, Horacio F Cantiello, María Del Rocío Cantero.
      Polycystin-2 (PC2, TRPP2) is a Ca2+ permeable nonselective cation channel whose dysfunction generates autosomal dominant polycystic kidney disease (ADPKD). PC2 is present in different cell locations, including the primary cilium of renal epithelial cells. However, little is known as to whether PC2 contributes to the primary cilium structure. Here, we explored the effect(s) of external Ca2+, PC2 channel blockers, and PKD2 gene silencing on the length of primary cilia in wild-type LLC-PK1 renal epithelial cells. Confluent cell monolayers were fixed and immuno-labeled with an anti-acetylated α-tubulin antibody to identify primary cilia and measure their length. Although primary cilia length measurements did not follow a Normal distribution, the data were normalized by Box-Cox transformation rendering statistical differences under all experimental conditions. Cells exposed to high external Ca2+ (6.2 mM) decreased a 13.5% (p < 0.001) primary cilia length as compared to controls (1.2 mM Ca2+). In contrast, the PC2 inhibitors amiloride (200 μM) and LiCl (10 mM), both increased primary ciliary length by 33.2% (p < 0.001), and 17.4% (p < 0.001), respectively. PKD2 gene silencing by siRNA elicited a statistically significant, 10.3% (p < 0.001) increase in primary cilia length compared to their respective scrambled RNA transfected cells. The data indicate that conditions that regulate PC2 function or gene expression modify the length of primary cilia in renal epithelial cells. Blocking of PC2 mitigates the effects of elevated external Ca2+ concentration on primary cilia length. Proper regulation of PC2 function in the primary cilium may be essential in the onset of mechanisms that trigger cyst formation in ADPKD.
    Keywords:  ADPKD; calcium; lithium; polycystin-2; primary cilia
    DOI:  https://doi.org/10.3389/fphys.2022.995473
  2. J Am Soc Nephrol. 2022 Oct 21. pii: ASN.2021091180. [Epub ahead of print]
    XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice.
    Matteus Krappitz, Rishi Bhardwaj, Ke Dong, Tobias Staudner, Duygu Elif Yilmaz, Carlotta Pioppini, Parisa Westergerling, David Ruemmele, Till Hollmann, Thuy Anh Nguyen, Yiqiang Cai, Anna-Rachel Gallagher, Stefan Somlo, Sorin Fedeles.
       BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in Pkd1 and Pkd2. They encode the polytopic integral membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which are expressed on primary cilia. Formation of kidney cysts in ADPKD starts when a somatic second hit mechanism inactivates the wild-type Pkd allele. Approximately one quarter of families with ADPDK due to Pkd1 have germline nonsynonymous amino acid substitution (missense) mutations. A subset of these mutations is hypomorphic, retaining some residual PC1 function. Previous studies have shown that the highly conserved Ire1α-XBP1 pathway of the unfolded protein response can modulate levels of functional PC1 in the presence of mutations in genes required for post-translational maturation of integral membrane proteins. We examine how activity of the endoplasmic reticulum chaperone-inducing transcription factor XBP1 affects ADPKD in a murine model with missense Pkd1.
    METHODS: We engineered a Pkd1 REJ domain missense murine model, Pkd1R2216W , on the basis of the orthologous human hypomorphic allele Pkd1R2220W , and examined the effects of transgenic activation of XBP1 on ADPKD progression.
    RESULTS: Expression of active XBP1 in cultured cells bearing PC1R2216W mutations increased levels and ciliary trafficking of PC1R2216W. Mice homozygous for Pkd1R2216W or heterozygous for Pkd1R2216W in trans with a conditional Pkd1fl allele exhibit severe ADPKD following inactivation in neonates or adults. Transgenic expression of spliced XBP1 in tubule segments destined to form cysts reduced cell proliferation and improved Pkd progression, according to structural and functional parameters.
    CONCLUSIONS: Modulating ER chaperone function through XBP1 activity improved Pkd in a murine model of PC1, suggesting therapeutic targeting of hypomorphic mutations.
    Keywords:  Ire1α-XBP1 pathway; chaperone; genetic renal disease; mutation; polycystic kidney disease; polycystin-1; protein folding; unfolded protein response
    DOI:  https://doi.org/10.1681/ASN.2021091180
  3. JHEP Rep. 2022 Nov;4(11): 100579
    Modelling polycystic liver disease progression using age-adjusted liver volumes and targeted mutational analysis.
    Dana Sierks, Ria Schönauer, Anja Friedrich, Elena Hantmann, Jonathan de Fallois, Nikolas Linder, Janett Fischer, Adam Herber, Carsten Bergmann, Thomas Berg, Jan Halbritter.
       Background & Aims: Polycystic liver disease (PLD) manifests as numerous fluid-filled cysts scattered throughout the liver parenchyma. PLD most commonly develops in females, either as an extra-renal manifestation of autosomal-dominant polycystic kidney disease (ADPKD) or as isolated autosomal-dominant polycystic liver disease (ADPLD). Despite known genetic causes, clinical variability challenges patient counselling and timely risk prediction is hampered by a lack of genotype-phenotype correlations and prognostic imaging classifications.
    Methods: We performed targeted next-generation sequencing and multiplex ligation-dependent probe amplification to identify the underlying genetic defect in a cohort of 80 deeply characterized patients with PLD. Identified genotypes were correlated with total liver and kidney volume (assessed by CT or MRI), organ function, co-morbidities, and clinical endpoints.
    Results: Monoallelic diagnostic variants were identified in 60 (75%) patients, 38 (48%) of which pertained to ADPKD-gene variants (PKD1, PKD2, GANAB) and 22 (27%) to ADPLD-gene variants (PRKCSH, SEC63). Disease severity defined by age at waitlisting for liver transplantation and first PLD-related hospitalization was significantly more pronounced in mutation carriers compared to patients without genetic diagnoses. While current imaging classifications proved unable to differentiate between severe and moderate courses, grouping by estimated age-adjusted total liver volume progression yielded significant risk discrimination.
    Conclusion: This study underlines the predictive value of providing a molecular diagnosis for patients with PLD. In addition, we propose a novel risk-classification model based on age- and height-adjusted total liver volume that could improve individual prognostication and personalized clinical management.
    Lay summary: Polycystic liver disease (PLD) is a highly variable condition that can be asymptomatic or severe. However, it is currently difficult to predict clinical outcomes such as hospitalization, symptom burden, and need for transplantation in individual patients. In the current study, we aimed to investigate the clinical value of genetic confirmation and an age-adjusted total liver volume classification for individual disease prediction. While genetic confirmation generally pointed to more severe disease, estimated age-adjusted increases in liver volume could be useful for predicting clinical outcomes.
    Keywords:  ACGS, Association for Clinical Genomic Sciences; ACMG, American College of Medical genetics and Genomics; ADPKD; ADPKD, autosomal-dominant polycystic kidney disease; ADPLD; ADPLD, autosomal-dominant polycystic liver disease; ESKD, end-stage kidney disease; GANAB; LRT, log-likelihood ratio test; LTx, liver transplantation; MCD, maximum cyst diameter; MELD, model for end-stage liver disease; MLPA, multiplex ligation-dependent probe amplification; OR, odds ratio; PCLD; PG, progression groups; PKD1; PKD1, polycystin 1; PKD2; PKD2, polycystin 2; PLD; PLD, polycystic liver disease; PRKCSH; SEC63; VUS, variants of uncertain significance; hTKV, height-adjusted total kidney volume; hTLV, height-adjusted total liver volume; hepatomegaly; nTKV, normalized total kidney volume; nTLV, normalized total liver volume; polycystic disease; polycystic kidney disease; tNGS, targeted next-generation sequencing; total liver volume
    DOI:  https://doi.org/10.1016/j.jhepr.2022.100579
  4. Biochem Biophys Res Commun. 2022 Oct 09. pii: S0006-291X(22)01412-7. [Epub ahead of print]635 1-11
    Synergistic effect of anticancer drug resistance and Wnt3a on primary ciliogenesis in A549 cell-derived anticancer drug-resistant subcell lines.
    Sun-Ok Kim, Bo Yeon Kim, Kyung Ho Lee.
      Primary cilia, antenna-like cellular sensor structures, are generated from the mother centriole in the G0/G1 cell-cycle phase under control by cellular signaling pathways involving Wnt, hedgehog, and platelet-derived growth factor. Although primary ciliary dynamics have been reported to be closely related to ciliopathy and tumorigenesis, the molecular basis for the role of primary cilia in human disease is lacking. To clarify how Wnt3a affects primary ciliogenesis in anticancer drug-resistant cells, we derived specific drug-resistant subcell lines from A549 human lung cancer cells using anticancer drugs doxorubicin, dasatinib, and paclitaxel (A549/Dox, A549/Das, and A549/Pac, respectively). The primary cilia-containing cell population and primary cilia length increased in the A549/Dox and A549/Pac subcell lines under increased MDR1 expression, when compared to those in the parental A549 cells. In the A549/Das subcell line, primary cilia length increased but the cell population was not affected. In addition, Wnt3a increased primary cilia-containing cell population and primary cilia length in A549/Dox, A549/Das, and A549/Pac cells, without change of cell growth. Abnormal shapes of primary cilia were frequently observed by anticancer drug resistance and Wnt3a stimulation. Taken together, our results indicate that anticancer drug resistance and Wnt3a affect primary ciliogenesis synergistically, suggesting a potential new strategy for overcoming anticancer drug resistance.
    Keywords:  Anticancer drug; Anticancer drug resistance; Primary cilia; Synergistic effect; Wnt3a
    DOI:  https://doi.org/10.1016/j.bbrc.2022.10.026
  5. BMC Nephrol. 2022 Oct 18. 23(1): 334
    A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease.
    Gregory Mader, Deirdre Mladsi, Myrlene Sanon, Molly Purser, Christine L Barnett, Dorothee Oberdhan, Terry Watnick, Stephen Seliger.
       BACKGROUND: Tolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking.
    METHODS: A model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death.
    RESULTS: When treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively.
    CONCLUSIONS: The model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression.
    Keywords:  Autosomal dominant polycystic kidney disease; Disease modeling; End-stage renal disease; Renal function decline; Tolvaptan
    DOI:  https://doi.org/10.1186/s12882-022-02956-8
  6. Front Med (Lausanne). 2022 ;9 987092
    Real clinical experience after one year of treatment with tolvaptan in patients with autosomal dominant polycystic kidney disease.
    Javier Naranjo, Francisco Borrego, José Luis Rocha, Mercedes Salgueira, Maria Adoración Martín-Gomez, Cristhian Orellana, Ana Morales, Fernando Vallejo, Pilar Hidalgo, Francisca Rodríguez, Remedios Garófano, Isabel González, Rafael Esteban, Mario Espinosa.
       Background: Tolvaptan (TV) is the first vasopressin-receptor antagonist approved for the treatment of autosomal dominant polycystic kidney disease (ADPKD). No publications report TV experience in real clinical practice during the first year of treatment.
    Methods: A prospective study of an initial cohort of 220 rapidly progressing patients treated with TV for 12 months. The tolerability of TV, the evolution of the estimated glomerular filtration rate (eGFR), analytical parameters, and blood pressure were analyzed.
    Results: A total of 163 patients (78.2%) received TV for 1 year. The main causes of treatment withdrawal were the aquaretic effects (11%), eGFR deterioration (5%), and hepatic toxicity (2.3%). eGFR decreased significantly after 1 month of treatment without further changes. The decrease in eGFR in the first month was higher in patients with an initially higher eGFR. The eGFR drop during the first year of treatment with TV was lower than that reported by patients in the 2 years prior to TV treatment (-1.7 ± 7.6 vs. -4.4 ± 4.8 mL/min, p = 0.003). Serum sodium and uric acid concentrations increased, and morning urinary osmolality decreased in the first month, with no further changes. Blood pressure decreased significantly without changes in antihypertensive medication.
    Conclusion: TV treatment is well tolerated by most patients. Liver toxicity is very rare and self-limited. TV reduces eGFR in the first month without showing further changes during the first year of treatment. Patients with a higher starting eGFR will suffer a greater initial drop, with a longer recovery. We suggest using the eGFR observed after a month of treatment as the reference for future comparisons and calculating the rate of eGFR decline in patients undergoing TV treatment.
    Keywords:  glomerular filtration rate (eGFR); hepatic toxicity; polycystic kidney disease (PKD); tolvaptan; urinary osmolality
    DOI:  https://doi.org/10.3389/fmed.2022.987092
  7. J Cell Sci. 2022 Oct 18. pii: jcs.259999. [Epub ahead of print]
    LRRK1-mediated NDEL1 phosphorylation promotes cilia disassembly via dynein-2-driven retrograde intraflagellar transport.
    Hiroshi Hanafusa, Shin Kedashiro, Mako Gotoh, Ko-Hei Saitoh, Hironori Inaba, Tomoki Nishioka, Kozo Kaibuchi, Masaki Inagaki, Naoki Hisamoto, Kunihiro Matsumoto.
      Primary cilia are antenna-like organelles that regulate growth and development via extracellular signals. However, the molecular mechanisms underlying cilia dynamics, particularly those regulating their disassembly, are not well understood. Here, we show that leucine-rich repeat kinase 1 (LRRK1) plays a role in regulating cilia disassembly. The depletion of LRRK1 impairs primary cilia resorption following serum stimulation in cultured cells. Polo-like kinase 1 (PLK1) plays an important role in this process. During ciliary resorption, PLK1 phosphorylates LRRK1 at the primary cilia base, resulting in its activation. We identified nuclear distribution protein nudE-like 1 (NDEL1), which is known to positively regulate cilia disassembly, as a target of LRRK1 phosphorylation. While LRRK1 phosphorylation of NDEL1 on Ser-155 promotes NDEL1 interaction with the intermediate chains of cytoplasmic dynein-2, it is also crucial for triggering ciliary resorption through dynein-2-driven retrograde intraflagellar transport. These findings provide evidence that the novel PLK1-LRRK1-NDEL1 pathway regulates cilia disassembly.
    Keywords:  LRRK1; NDEL1; Primary cilia
    DOI:  https://doi.org/10.1242/jcs.259999
  8. J Cell Sci. 2022 Oct 21. pii: jcs.260073. [Epub ahead of print]
    Disease-associated mutations in WDR34 lead to diverse impacts on the assembly and function of dynein-2.
    Caroline Shak, Laura Vuolo, Borhan Uddin, Yohei Katoh, Tom Brown, Aakash G Mukhopadhyay, Kate Heesom, Anthony J Roberts, Nicola Stevenson, Kazuhisa Nakayama, David J Stephens.
      The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport in the primary cilium result in ciliopathies, a group of genetic disorders that commonly lead to the malformation of organs such as the kidney, liver and eyes and skeletal dysplasias. Motor proteins dynein-2 and kinesin-2 mediate retrograde and anterograde transport respectively in the cilium. WDR34, a dynein-2 intermediate chain, is required for the maintenance of cilia function. Here, we investigated WDR34 mutations identified in Jeune syndrome, short-rib polydactyly syndrome or asphyxiating thoracic dysplasia patients. There is a poor correlation between genotype and phenotype in these cases making diagnosis and treatment highly complex. We set out to define the biological impacts on cilia formation and function of WDR34 mutations by stably expressing the mutant proteins in WDR34 knockout cells. WDR34 mutations led to different spectrums of phenotypes. Quantitative proteomics demonstrated changes in dynein-2 assembly, whereas initiation and extension of the axoneme, localization of intraflagellar transport complex-B proteins, transition zone integrity, and Hedgehog signalling were also affected.
    Keywords:  Cilia; Dynein-2; WDR34; ciliopathy; microtubule motor
    DOI:  https://doi.org/10.1242/jcs.260073
  9. Adv Biol Regul. 2022 Oct 04. pii: S2212-4926(22)00059-8. [Epub ahead of print] 100919
    Novel aspects of intra-islet communication: Primary cilia and filopodia.
    Noah Moruzzi, Barbara Leibiger, Christopher J Barker, Ingo B Leibiger, Per-Olof Berggren.
      Pancreatic islets are micro-organs composed of a mixture of endocrine and non-endocrine cells, where the former secrete hormones and peptides necessary for metabolic homeostasis. Through vasculature and innervation the cells within the islets are in communication with the rest of the body, while they interact with each other through juxtacrine, paracrine and autocrine signals, resulting in fine-tuned sensing and response to stimuli. In this context, cellular protrusion in islet cells, such as primary cilia and filopodia, have gained attention as potential signaling hubs. During the last decade, several pieces of evidence have shown how the primary cilium is required for islet vascularization, function and homeostasis. These findings have been possible thanks to the development of ciliary/basal body specific knockout models and technological advances in microscopy, which allow longitudinal monitoring of engrafted islets transplanted in the anterior chamber of the eye in living animals. Using this technique in combination with optogenetics, new potential paracrine interactions have been suggested. For example, reshaping and active movement of filopodia-like protrusions of δ-cells were visualized in vivo, suggesting a continuous cell remodeling to increase intercellular contacts. In this review, we discuss these recent discoveries regarding primary cilia and filopodia and their role in islet homeostasis and intercellular islet communication.
    DOI:  https://doi.org/10.1016/j.jbior.2022.100919
  10. Cell Mol Life Sci. 2022 Oct 19. 79(11): 556
    Arl13b controls basal cell stemness properties and Hedgehog signaling in the mouse epididymis.
    Laura Girardet, Daniel G Cyr, Clémence Belleannée.
      Epithelial cells orchestrate a series of intercellular signaling events in response to tissue damage. While the epididymis is composed of a pseudostratified epithelium that controls the acquisition of male fertility, the maintenance of its integrity in the context of tissue damage or inflammation remains largely unknown. Basal cells of the epididymis contain a primary cilium, an organelle that controls cellular differentiation in response to Hedgehog signaling cues. Hypothesizing its contribution to epithelial homeostasis, we knocked out the ciliary component ARL13B in keratin 5-positive basal cells. In this model, the reduced size of basal cell primary cilia was associated with impaired Hedgehog signaling and the loss of KRT5, KRT14, and P63 basal cell markers. When subjected to tissue injury, the epididymal epithelium from knock-out mice displayed imbalanced rates of cell proliferation/apoptosis and failed to properly regenerate in vivo. This response was associated with changes in the transcriptomic landscape related to immune response, cell differentiation, cell adhesion, and triggered severe hypoplasia of the epithelium. Together our results indicate that the ciliary GTPase, ARL13B, participates in the transduction of the Hedgehog signaling pathway to maintain basal cell stemness needed for tissue regeneration. These findings provide new insights into the role of basal cell primary cilia as safeguards of pseudostratified epithelia.
    Keywords:  Basal cell; Epididymis; Hedgehog signaling; Primary cilia; Resident stem cells; Tissue regeneration
    DOI:  https://doi.org/10.1007/s00018-022-04570-1
  11. J Cell Physiol. 2022 Oct 17.
    ATM- and ATR-induced primary ciliogenesis promotes cisplatin resistance in pancreatic ductal adenocarcinoma.
    Yu-Ying Chao, Bu-Miin Huang, I-Chen Peng, Pei-Rong Lee, Yi-Shyun Lai, Wen-Tai Chiu, Yi-Syuan Lin, Shih-Chieh Lin, Jung-Hsuan Chang, Pai-Sheng Chen, Shaw-Jenq Tsai, Chia-Yih Wang.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of its late diagnosis and chemoresistance. Primary cilia, the cellular antennae, are observed in most human cells to maintain development and differentiation. Primary cilia are gradually lost during the progression of pancreatic cancer and are eventually absent in PDAC. Here, we showed that cisplatin-resistant PDAC regrew primary cilia. Additionally, genetic or pharmacological disruption of primary cilia sensitized PDAC to cisplatin treatment. Mechanistically, ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR), tumor suppressors that initiate DNA damage responses, promoted the excessive formation of centriolar satellites (EFoCS) and autophagy activation. Disruption of EFoCS and autophagy inhibited primary ciliogenesis, sensitizing PDAC cells to cisplatin treatment. Collectively, our findings revealed an unexpected interplay among the DNA damage response, primary cilia, and chemoresistance in PDAC and deciphered the molecular mechanism by which ATM/ATR-mediated EFoCS and autophagy cooperatively regulate primary ciliogenesis.
    Keywords:  DNA damage response; autophagy; centriolar satellites; chemoresistance; pancreatic ductal adenocarcinoma; primary cilia
    DOI:  https://doi.org/10.1002/jcp.30898
  12. Front Genet. 2022 ;13 985227
    CFAP300 mutation causing primary ciliary dyskinesia in Finland.
    Rüdiger Schultz, Varpu Elenius, Mahmoud R Fassad, Grace Freke, Andrew Rogers, Amelia Shoemark, Tiina Koistinen, Mai A Mohamed, Jacqueline S Y Lim, Hannah M Mitchison, Anu I Sironen.
      Primary ciliary dyskinesia (PCD) is a rare genetic condition characterized by chronic respiratory tract infections and in some cases laterality defects and infertility. The symptoms of PCD are caused by malfunction of motile cilia, hair-like organelles protruding out of the cell that are responsible for removal of mucus from the airways and organizing internal organ positioning during embryonic development. PCD is caused by mutations in genes coding for structural or assembly proteins in motile cilia. Thus far mutations in over 50 genes have been identified and these variants explain around 70% of all known cases. Population specific genetics underlying PCD has been reported, thus highlighting the importance of characterizing gene variants in different populations for development of gene-based diagnostics. In this study, we identified a recurrent loss-of-function mutation c.198_200delinsCC in CFAP300 causing lack of the protein product. PCD patients homozygous for the identified CFAP300 mutation have immotile airway epithelial cilia associated with missing dynein arms in their ciliary axonemes. Furthermore, using super resolution microscopy we demonstrate that CFAP300 is transported along cilia in normal human airway epithelial cells suggesting a role for CFAP300 in dynein complex transport in addition to preassembly in the cytoplasm. Our results highlight the importance of CFAP300 in dynein arm assembly and improve diagnostics of PCD in Finland.
    Keywords:  CFAP300; diagnostics; dynein arm preassembly; motile cilia; primary ciliary dyskinesia
    DOI:  https://doi.org/10.3389/fgene.2022.985227
  13. Toxicol Lett. 2022 Oct 13. pii: S0378-4274(22)01762-3. [Epub ahead of print]371 38-45
    Fasudil, a ROCK inhibitor, prevents neuropathic pain in Minamata disease model rats.
    Masatake Fujimura.
      Methylmercury (MeHg), an environmental toxicant, is known to cause sensory impairment by inducing neurodegeneration of sensory nervous systems. However, in recent years, it has been revealed that neuropathic pain occurs in the chronic phase of MeHg poisoning, that is, in current Minamata disease patients. Our recent study using Minamata disease model rats demonstrated that MeHg-mediated neurodegeneration in the sensory nervous system may induce inflammatory microglia production in the dorsal horn of the spinal cord and subsequent somatosensory cortical rewiring, leading to neuropathic pain. We hypothesized that inhibition of the Rho-associated coiled coil-forming protein kinase (ROCK) pathway could prevent MeHg-induced neuropathic pain because the ROCK pathway is known to be involved in inducing the production of inflammatory microglia. Here, we showed for the first time that Fasudil, a ROCK inhibitor, can prevent neuropathic pain in Minamata disease model rats. In this model, Fasudil significantly suppressed nerve injury-induced inflammatory microglia production in the dorsal horn of the spinal cord and prevented subsequent somatosensory cortical rewiring. These results suggest that the ROCK pathway is involved in the onset and development of neuropathic pain in the chronic phase of Minamata disease, and that its inhibition is effective in pain prevention.
    Keywords:  Inflammatory microglia; Methylmercury; Neuropathic pain; ROCK inhibitor
    DOI:  https://doi.org/10.1016/j.toxlet.2022.10.001
  14. Balkan J Med Genet. 2021 Nov;24(2): 83-87
    Having Multiple Renal Cysts in a Young Adult is not Always a Sign of Polycystic Kidney Disease.
    K Kaynar, S Kayıpmaz, A H Çebi, Ş Hüseynova.
      Multiple renal cysts in adult patients could have asymptomatic, benign and a nonprogressive course. However, these cysts could be renal features of a very rare hereditary, progressive syndrome defined as cranioectodermal dysplasia (CED or Sensenbrenner syndrome). Affected patients show dysmorphic features such as craniosynostosis, nail dystrophy, cutaneous dyshydrosis, dry or scaly palmar skin, trichodysplasia, deafness, pectus excavatum, telecanthus, hypertelorism, low set ears, everted lower lip, anteverted nares, short neck and height, joint laxity, inguinal hernia, widely spaced teeth, microdontia, hypodontia in addition to nephronophthisis. We report a 22-year-old male hypertensive patient with multiple renal cysts and dental malformations listed as malocclusion, screwdriver shaped crowns, widely spaced front teeth, microdontia and hyperdontia. Molecular analysis reported missense p.(Ala875Thr) and p.(Lys969Asn) variants in the WDR35 gene. The 1-year follow-up of this case provided the knowledge that angiotensin II receptor blocker drug (olmesartan) reduced the microalbuminuria to normal levels and preserved the renal functions. We suggest interdisciplinary studies, especially intraoral and genetic evaluations for patients with cystic renal diseases. For the first time we report that hyperdontia could be found as a dental feature of CED.
    Keywords:  Ciliopathies; Cranioectodermal dysplasia (CED); Cystic; Kidney diseases; Syndrome
    DOI:  https://doi.org/10.2478/bjmg-2021-0016
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