bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–08–27
fiveteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. The Case | A patient with autosomal dominant polycystic kidney disease with an atypical kidney magnetic resonance image.
  2. Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.
  3. Haemosuccus pancreaticus associated with autosomal dominant polycystic kidney disease and chronic pancreatitis.
  4. Co-Inheritance of Pathogenic Variants in PKD1 and PKD2 Genes Determined by Parental Segregation and De Novo Origin: A Case Report.
  5. Participant Perceptions in a Long-term Clinical Trial of Autosomal Dominant Polycystic Kidney Disease.
  6. Automated prognosis of renal function decline in ADPKD patients using deep learning.
  7. The IFT81-IFT74 complex acts as an unconventional RabL2 GTPase-activating protein during intraflagellar transport.
  8. Restoring Ciliary Function: Gene Therapeutics for Primary Ciliary Dyskinesia.
  9. Ultrastructural Visualization of Resin-embedded Primary Cilia by Serial Section Electron Tomography.
  10. Animal evolution: No cilia, no problem!
  11. A Novel Genetic Variant in MBD5 Associated with Severe Epilepsy and Intellectual Disability: Potential Implications on Neural Primary Cilia.
  12. Amyloid-β slows cilia movement along the ventricle, impairs fluid flow, and exacerbates its neurotoxicity in explant culture.
  13. [177Lu]Lu-PSMA-617 Therapy in a Patient with Chronic Kidney Disease.
  14. Mutational burden of XPNPEP3 leads to defects in mitochondrial complex I and cilia in NPHPL1.
  15. Diagnosis of cardiovascular disease in patients with chronic kidney disease.
  1. Kidney Int. 2023 Sep;pii: S0085-2538(23)00468-4. [Epub ahead of print]104(3): 625-626
    The Case | A patient with autosomal dominant polycystic kidney disease with an atypical kidney magnetic resonance image.
    Eleonora Riccio, Massimo Imbriaco, Aurora Daniele, Guido Iaccarino, Antonio Pisani.
      
    DOI:  https://doi.org/10.1016/j.kint.2023.06.014
  2. Kidney Int. 2023 Aug 18. pii: S0085-2538(23)00559-8. [Epub ahead of print]
    Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.
    Genomics England Research Consortium
      Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals. Nek8 knockout mouse kidney epithelial (IMCD3) cells transfected with wild type and variant NEK8 were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrent de novo mutations of the NEK8 missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein or all variant forms of the protein expressed in Nek8 knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However, Nek8 knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal protein ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activity in vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.
    Keywords:  NEK8; ciliopathy; kinase; polycystic kidney disease
    DOI:  https://doi.org/10.1016/j.kint.2023.07.021
  3. BMJ Case Rep. 2023 08 22. pii: e255855. [Epub ahead of print]16(8):
    Haemosuccus pancreaticus associated with autosomal dominant polycystic kidney disease and chronic pancreatitis.
    Haruki Mae, Toshinori Nishizawa, Rikako Wakai, Hiroko Arioka.
      
    Keywords:  GI bleeding; Pancreas and biliary tract
    DOI:  https://doi.org/10.1136/bcr-2023-255855
  4. Genes (Basel). 2023 Aug 06. pii: 1589. [Epub ahead of print]14(8):
    Co-Inheritance of Pathogenic Variants in PKD1 and PKD2 Genes Determined by Parental Segregation and De Novo Origin: A Case Report.
    Ludovico Graziani, Stefania Zampatti, Miriam Lucia Carriero, Chiara Minotti, Cristina Peconi, Mario Bengala, Emiliano Giardina, Giuseppe Novelli.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, and it is typically caused by PKD1 and PKD2 heterozygous variants. Nonetheless, the extensive phenotypic variability observed among affected individuals, even within the same family, suggests a more complex pattern of inheritance. We describe an ADPKD family in which the proband presented with an earlier and more severe renal phenotype (clinical diagnosis at the age of 14 and end-stage renal disease aged 24), compared to the other affected family members. Next-generation sequencing (NGS)-based analysis of polycystic kidney disease (PKD)-associated genes in the proband revealed the presence of a pathogenic PKD2 variant and a likely pathogenic variant in PKD1, according to the American College of Medical Genetics and Genomics (ACMG) criteria. The PKD2 nonsense p.Arg872Ter variant was segregated from the proband's father, with a mild phenotype. A similar mild disease presentation was found in the proband's aunts and uncle (the father's siblings). The frameshift p.Asp3832ProfsTer128 novel variant within PKD1 carried by the proband in addition to the pathogenic PKD2 variant was not found in either parent. This report highlights that the co-inheritance of two or more PKD genes or alleles may explain the extensive phenotypic variability among affected family members, thus emphasizing the importance of NGS-based techniques in the definition of the prognostic course.
    Keywords:  ADPKD; NGS; PKD1/2; digenic disease; genotype–phenotype correlations
    DOI:  https://doi.org/10.3390/genes14081589
  5. Kidney Med. 2023 Sep;5(9): 100691
    Participant Perceptions in a Long-term Clinical Trial of Autosomal Dominant Polycystic Kidney Disease.
    Sneha Amin, Irene Sangadi, Margaret Allman-Farinelli, Sunil V Badve, Neil Boudville, Helen Coolican, Susan Coulshed, Sheryl Foster, Mangalee Fernando, Imad Haloob, David C H Harris, Carmel M Hawley, Jane Holt, Martin Howell, Karthik Kumar, David W Johnson, Vincent W Lee, Jun Mai, Anna Rangan, Simon D Roger, Kamal Sud, Vicente Torres, Eswari Vilayur, Gopala K Rangan.
       Rationale & Objective: The development of new therapies for autosomal dominant polycystic kidney disease requires clinical trials to be conducted efficiently. In this study, the factors affecting the recruitment and retention of participants enrolled in a 3-year randomized controlled trial in autosomal dominant polycystic kidney disease were investigated.
    Study Design: Qualitative study.
    Setting & Participants: All participants (N=187) were invited to complete a 16-item questionnaire at the final study visit of the primary trial. Participants were recruited to complete a semistructured interview using purposeful sampling according to age, self-reported gender, and randomization group.
    Analytical Approach: Descriptive statistics were used for demographic data and questionnaires. The interview transcripts underwent inductive thematic coding.
    Results: One hundred and forty-six of the 187 randomized participants (79%) completed the post-trial questionnaire, and 31 of the 187 participants (21%) completed the interview. Most participants (94%) rated their global satisfaction with the trial as high (a score of 8 or more out of 10). Altruism, knowledge gain, and access to new treatments were the main motivators for recruitment. The main reasons for considering leaving the study were concerns about the risk of intervention and family or work issues. Strategies that favored retention included flexibility in attending different study sites, schedule flexibility, staff interactions, and practical support with parking and reminders. The main burden was time away from work with lost wages, and burden associated with magnetic resonance imaging scans and 24-hour urine output collections.
    Limitations: The study population was restricted to participants in a single nondrug clinical trial, and the results could be influenced by selection and possible social desirability bias.
    Conclusions: Participants reported high levels of satisfaction that occurred as a function of the trial meeting participants' expectations. Furthermore, retention was a balance between the perceived benefits and burden of participation. Consideration of these perspectives in the design of future clinical trials will improve their efficiency and conduct.
    Plain-Language Summary: Advances in the clinical practice of autosomal dominant polycystic kidney disease (ADPKD) require affected individuals to voluntarily participate in long-term multicenter randomized controlled trials (RCTs). In this qualitative post hoc study of a 3-year RCT of increased water intake in ADPKD, altruism, knowledge gain, and access to a nondrug treatment positively influenced the decision to volunteer. Ongoing participation was enabled by building flexibility into the study protocol and staff prioritizing a participant's needs during study visits. Although participants completed the required tests, most were considered burdensome. This study highlights the importance of incorporating protocol flexibility into trial design; the preference for interventions with a low risk of adverse effects; and the urgent requirement for robust surrogate noninvasive biomarkers to enable shorter RCTs in ADPKD.
    Keywords:  Autosomal dominant polycystic kidney disease; clinical trials; participant experience; participant perspective; patient-centered care; qualitative research; trial design
    DOI:  https://doi.org/10.1016/j.xkme.2023.100691
  6. Z Med Phys. 2023 Aug 21. pii: S0939-3889(23)00090-9. [Epub ahead of print]
    Automated prognosis of renal function decline in ADPKD patients using deep learning.
    Anish Raj, Fabian Tollens, Anna Caroli, Dominik Nörenberg, Frank G Zöllner.
      An accurate prognosis of renal function decline in Autosomal Dominant Polycystic Kidney Disease (ADPKD) is crucial for early intervention. Current biomarkers used are height-adjusted total kidney volume (HtTKV), estimated glomerular filtration rate (eGFR), and patient age. However, manually measuring kidney volume is time-consuming and subject to observer variability. Additionally, incorporating automatically generated features from kidney MRI images, along with conventional biomarkers, can enhance prognostic improvement. To address these issues, we developed two deep-learning algorithms. Firstly, an automated kidney volume segmentation model accurately calculates HtTKV. Secondly, we utilize segmented kidney volumes, predicted HtTKV, age, and baseline eGFR to predict chronic kidney disease (CKD) stages >=3A, >=3B, and a 30% decline in eGFR after 8 years from the baseline visit. Our approach combines a convolutional neural network (CNN) and a multi-layer perceptron (MLP). Our study included 135 subjects and the AUC scores obtained were 0.96, 0.96, and 0.95 for CKD stages >=3A, >=3B, and a 30% decline in eGFR, respectively. Furthermore, our algorithm achieved a Pearson correlation coefficient of 0.81 between predicted and measured eGFR decline. We extended our approach to predict distinct CKD stages after eight years with an AUC of 0.97. The proposed approach has the potential to enhance monitoring and facilitate prognosis in ADPKD patients, even in the early disease stages.
    Keywords:  Autosomal dominant polycystic kidney disease; Chronic kidney disease; Deep learning; Image classification; Regression; Total kidney volume
    DOI:  https://doi.org/10.1016/j.zemedi.2023.08.001
  7. EMBO J. 2023 Aug 22. e111807
    The IFT81-IFT74 complex acts as an unconventional RabL2 GTPase-activating protein during intraflagellar transport.
    Niels Boegholm, Narcis A Petriman, Marta Loureiro-López, Jiaolong Wang, Miren Itxaso Santiago Vela, Beibei Liu, Tomoharu Kanie, Roy Ng, Peter K Jackson, Jens S Andersen, Esben Lorentzen.
      Cilia are important cellular organelles for signaling and motility and are constructed via intraflagellar transport (IFT). RabL2 is a small GTPase that localizes to the basal body of cilia via an interaction with the centriolar protein CEP19 before downstream association with the IFT machinery, which is followed by initiation of IFT. We reconstituted and purified RabL2 with CEP19 or IFT proteins to show that a reconstituted pentameric IFT complex containing IFT81/74 enhances the GTP hydrolysis rate of RabL2. The binding site on IFT81/74 that promotes GTP hydrolysis in RabL2 was mapped to a 70-amino-acid-long coiled-coil region of IFT81/74. We present structural models for RabL2-containing IFT complexes that we validate in vitro and in cellulo and demonstrate that Chlamydomonas IFT81/74 enhances GTP hydrolysis of human RabL2, suggesting an ancient evolutionarily conserved activity. Our results provide an architectural understanding of how RabL2 is incorporated into the IFT complex and a molecular rationale for why RabL2 dissociates from anterograde IFT trains soon after departure from the ciliary base.
    Keywords:  Cilium; GAP; GTPase; RabL2; intraflagellar transport
    DOI:  https://doi.org/10.15252/embj.2022111807
  8. Hum Gene Ther. 2023 Aug 25.
    Restoring Ciliary Function: Gene Therapeutics for Primary Ciliary Dyskinesia.
    Nicholas W Keiser, Erin Cant, Sneha Sitaraman, Amelia Shoemark, Maria P Limberis.
      Primary ciliary dyskinesia (PCD) is a genetic disease characterized by defects in motile cilia, that play an important role in several organ systems. Lung disease is a hallmark of PCD, given the essential role of cilia in airway surface defense. Diagnosis of PCD is complicated due to its reliance on complex tests that are not utilized by every clinic and also its phenotypic overlap with several other respiratory diseases. Nonetheless, PCD is increasingly being recognized as more common than once thought. The disease is genetically complex, with several genes reported to be associated with PCD. There is no cure for PCD, but gene therapy remains a promising therapeutic strategy. In this review we provide an overview of the clinical symptoms, diagnosis, genetics, and current treatment regimens for PCD. We also describe PCD model systems and discuss the therapeutic potential of different gene therapeutics for targeting the intended cellular target, the ciliated cells of the airway.
    DOI:  https://doi.org/10.1089/hum.2023.102
  9. Microsc Microanal. 2023 Jul 22. 29(Supplement_1): 1197-1198
    Ultrastructural Visualization of Resin-embedded Primary Cilia by Serial Section Electron Tomography.
    Shufeng Sun, Haixin Sui.
      
    DOI:  https://doi.org/10.1093/micmic/ozad067.616
  10. Curr Biol. 2023 08 21. pii: S0960-9822(23)00860-6. [Epub ahead of print]33(16): R863-R865
    Animal evolution: No cilia, no problem!
    Varsha Mathur.
      Cilia are fundamental organelles of eukaryotes with diverse functions spanning from cell motility to sensory perception. A new study presenting genomes from parasitic horsehair worms reveals highly reduced genomes that have lost the molecular machinery needed to make cilia.
    DOI:  https://doi.org/10.1016/j.cub.2023.06.074
  11. Int J Mol Sci. 2023 Aug 09. pii: 12603. [Epub ahead of print]24(16):
    A Novel Genetic Variant in MBD5 Associated with Severe Epilepsy and Intellectual Disability: Potential Implications on Neural Primary Cilia.
    Mariana Martins, Ana Rafaela Oliveira, Solange Martins, José Pedro Vieira, Pedro Perdigão, Ana Rita Fernandes, Luís Pereira de Almeida, Paulo Jorge Palma, Diana Bela Sequeira, João Miguel Marques Santos, Frederico Duque, Guiomar Oliveira, Ana Luísa Cardoso, João Peça, Catarina Morais Seabra.
      Disruptions in the MBD5 gene have been linked with an array of clinical features such as global developmental delay, intellectual disability, autistic-like symptoms, and seizures, through unclear mechanisms. MBD5 haploinsufficiency has been associated with the disruption of primary cilium-related processes during early cortical development, and this has been reported in many neurodevelopmental disorders. In this study, we describe the clinical history of a 12-year-old child harboring a novel MBD5 rare variant and presenting psychomotor delay and seizures. To investigate the impact of MBD5 haploinsufficiency on neural primary cilia, we established a novel patient-derived cell line and used CRISPR-Cas9 technology to create an isogenic control. The patient-derived neural progenitor cells revealed a decrease in the length of primary cilia and in the total number of ciliated cells. This study paves the way to understanding the impact of MBD5 haploinsufficiency in brain development through its potential impact on neural primary cilia.
    Keywords:  MBD5; epilepsy; neural cell models; neurodevelopment; primary cilia
    DOI:  https://doi.org/10.3390/ijms241612603
  12. Sci Rep. 2023 Aug 21. 13(1): 13586
    Amyloid-β slows cilia movement along the ventricle, impairs fluid flow, and exacerbates its neurotoxicity in explant culture.
    Ryota Makibatake, Sora Oda, Yoshiki Yagi, Hitoshi Tatsumi.
      Alzheimer's disease (AD) is characterized by extensive and selective death of neurons and deterioration of synapses and circuits in the brain. The Aβ1-42 concentration is higher in an AD brain than in cognitively normal elderly individuals, and Aβ1-42 exhibits neurotoxicity. Brain-derived Aβ is transported into the cerebrospinal fluid (CSF), and CSF flow is driven in part by the beating of cilia and CSF secretion into ventricles. Ventricles are lined with ependyma whose apical surface is covered with motile cilia. Herein, we constructed an experimental system to measure the movement of ependymal cilia and examined the effects of Aβ1-42 to the beating of cilia and neurons. The circadian rhythm of the beating frequency of ependymal cilia was detected using brain wall explant-cultures containing ependymal cilia and neurons; the beating frequency was high at midday and low at midnight. Aβ1-42 decreased the peak frequency of ciliary beating at midday and slightly increased it at midnight. Aβ1-42 exhibited neurotoxicity to neurons on the non-ciliated side of the explant culture, while the neurotoxicity was less evident in neurons on the ciliated side. The neurotoxic effect of Aβ1-42 was diminished when 1 mPa of shear stress was generated using a flow chamber system that mimicked the flow by cilia. These results indicate that Aβ1-42 affects the circadian rhythm of ciliary beating, decreases the medium flow by the cilia-beating, and enhances the neurotoxic action of Aβ1-42 in the brain explant culture.
    DOI:  https://doi.org/10.1038/s41598-023-40742-0
  13. J Nucl Med. 2023 Aug 24. pii: jnumed.123.265577. [Epub ahead of print]
    [177Lu]Lu-PSMA-617 Therapy in a Patient with Chronic Kidney Disease.
    Lorenzo Mercolli, Clemens Mingels, Giulia Manzini, Paul Cumming, Konstantinos Zeimpekis, Song Xue, Ian Alberts, Dominik Uehlinger, Axel Rominger, Kuangyu Shi, Ali Afshar-Oromieh.
      We report the dosimetric evaluation of prostate-specific membrane antigen-based radioligand therapy (RLT) for metastatic prostate cancer in a patient with autosomal-dominant polycystic kidney disease. Methods: The patient received hemodialysis during each of 6 RLT cycles while staying as an inpatient. We used voxel dosimetry and blood sampling for the dose calculation. Results: The patient responded well to the RLT, as indicated by the prostate-specific antigen level decreasing from 298 to 7.1 ng/mL. The doses per cycle ranged from 0.19 to 0.4 Gy/GBq for the parotid gland, 0.14 to 0.28 Gy/GBq for the submandibular gland, 0.03 to 0.11 Gy/GBq per kidney, and 0.10 to 0.15 Gy/GBq for the red bone marrow. Conclusion: This case suggests that [177Lu]Lu-PSMA-based RLT can be applied successfully and safely to a patient with chronic kidney disease undergoing hemodialysis.
    Keywords:  177Lu; chronic kidney disease; dosimetry; kidney failure; prostate-specific membrane antigen; radioligand therapy
    DOI:  https://doi.org/10.2967/jnumed.123.265577
  14. iScience. 2023 Aug 18. 26(8): 107446
    Mutational burden of XPNPEP3 leads to defects in mitochondrial complex I and cilia in NPHPL1.
    Lingxiao Tong, Jia Rao, Chenxi Yang, Jie Xu, Yijun Lu, Yuchen Zhang, Xiaohui Cang, Shanshan Xie, Jianhua Mao, Pingping Jiang.
      Nephronophthisis-like nephropathy-1 (NPHPL1) is a rare ciliopathy, caused by mutations of XPNPEP3. Despite a well-described monogenic etiology, the pathogenesis of XPNPEP3 associated with mitochondrial and ciliary function remains elusive. Here, we identified novel compound heterozygous mutations in NPHPL1 patients with renal lesion only or with extra bone cysts together. Patient-derived lymphoblasts carrying c.634G>A and c.761G>T together exhibit elevated mitochondrial XPNPEP3 levels via the reduction of mRNA degradation, leading to mitochondrial dysfunction in both urine tubular epithelial cells and lymphoblasts from patient. Mitochondrial XPNPEP3 was co-immunoprecipitated with respiratory chain complex I and was required for the stability and activity of complex I. Deletion of Xpnpep3 in mice resulted in lower activity of complex I, elongated primary cilium, and predisposition to tubular dilation and fibrosis under stress. Our findings provide valuable insights into the mitochondrial functions involved in the pathogenesis of NPHP.
    Keywords:  cell biology; disease; human Genetics
    DOI:  https://doi.org/10.1016/j.isci.2023.107446
  15. Nat Rev Nephrol. 2023 Aug 23.
    Diagnosis of cardiovascular disease in patients with chronic kidney disease.
    Carmine Zoccali, Patrick B Mark, Pantelis Sarafidis, Rajiv Agarwal, Marcin Adamczak, Rodrigo Bueno de Oliveira, Ziad A Massy, Peter Kotanko, Charles J Ferro, Christoph Wanner, Michel Burnier, Raymond Vanholder, Francesca Mallamaci, Andrzej Wiecek.
      Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD) and cardiovascular death. Identifying and monitoring cardiovascular complications and hypertension is important for managing patients with CKD or kidney failure and transplant recipients. Biomarkers of myocardial ischaemia, such as troponins and electrocardiography (ECG), have limited utility for diagnosing cardiac ischaemia in patients with advanced CKD. Dobutamine stress echocardiography, myocardial perfusion scintigraphy and dipyridamole stress testing can be used to detect coronary disease in these patients. Left ventricular hypertrophy and left ventricular dysfunction can be detected and monitored using various techniques with differing complexity and cost, including ECG, echocardiography, nuclear magnetic resonance, CT and myocardial scintigraphy. Atrial fibrillation and other major arrhythmias are common in all stages of CKD, and ambulatory heart rhythm monitoring enables precise time profiling of these disorders. Screening for cerebrovascular disease is only indicated in asymptomatic patients with autosomal dominant polycystic kidney disease. Standardized blood pressure is recommended for hypertension diagnosis and treatment monitoring and can be complemented by ambulatory blood pressure monitoring. Judicious use of these diagnostic techniques may assist clinicians in detecting the whole range of cardiovascular alterations in patients with CKD and enable timely treatment of CVD in this high-risk population.
    DOI:  https://doi.org/10.1038/s41581-023-00747-4
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