bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–01–29
thirteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Polycystic Kidney Disease Drug Development: A Conference Report.
  2. Radial pseudoaneurysm following coronary angiography in a patient with autosomal dominant polycystic kidney disease.
  3. Caregiver Burden of Autosomal Dominant Polycystic Kidney Disease: A Qualitative Study.
  4. Hypomorphic PKD1 alleles impact disease variability in autosomal dominant polycystic kidney disease.
  5. Predominant Liver Cystic Disease in a New Heterozygotic PKHD1 Variant: A Case Report.
  6. Novel method for the genomic analysis of PKD1 mutation in autosomal dominant polycystic kidney disease.
  7. MRAP2 regulates energy homeostasis by promoting primary cilia localization of MC4R.
  8. Primary cilia are WNT-transducing organelles whose biogenesis is controlled by a WNT-PP1 axis.
  9. Ciliary signaling proteins are mislocalized in the brains of Bardet-Biedl syndrome 1-null mice.
  10. Characterization of Primary Cilia Formation in Human ESC-Derived Retinal Organoids.
  11. Corrigendum to "Ttc21b deficiency attenuates autosomal dominant polycystic kidney disease in a kidney tubular- and maturation-dependent manner." Kidney Int. 2022;102:577-591.
  12. Renal cell carcinoma in end-stage renal disease: A retrospective study in patients from Hungary.
  13. Building train carriages for ciliary transport: (IFT-)A complex task.
  1. Kidney Med. 2023 Mar;5(3): 100596
    Polycystic Kidney Disease Drug Development: A Conference Report.
    Max C Liebau, Djalila Mekahli, Ronald Perrone, Belle Soyfer, Sorin Fedeles.
      Autosomal dominant polycystic kidney disease (ADPKD) is part of a spectrum of inherited diseases that also includes autosomal recessive polycystic kidney disease, autosomal dominant polycystic liver disease, and an expanding group of recessively inherited disorders collectively termed hepatorenal fibrocystic disorders. ADPKD is the most common monogenic disorder frequently leading to chronic kidney failure with an estimated prevalence of 12 million people worldwide. Currently, only one drug (tolvaptan) has been approved by regulatory agencies as disease-modifying therapy for ADPKD, but, given its mechanism of action and side effect profile, the need for an improved therapy for ADPKD remains a priority. Although significant regulatory progress has been made, with qualification of total kidney volume as a prognostic enrichment biomarker and its later designation as a reasonably likely surrogate endpoint for progression of ADPKD within clinical trials, further work is needed to accelerate drug development efforts for all forms of PKD. In May 2021, the PKD Outcomes Consortium at the Critical Path Institute and the PKD Foundation organized a PKD Regulatory Summit to spur conversations among patients, industry, academic, and regulatory stakeholders regarding future development of tools and drugs for ADPKD and autosomal recessive polycystic kidney disease. This Special Report reviews the key points discussed during the summit and provides future direction related to PKD drug development tools.
    DOI:  https://doi.org/10.1016/j.xkme.2022.100596
  2. Clin Res Cardiol. 2023 Jan 23.
    Radial pseudoaneurysm following coronary angiography in a patient with autosomal dominant polycystic kidney disease.
    Insa E Emrich, Michael Böhm, Felix Mahfoud.
      
    DOI:  https://doi.org/10.1007/s00392-023-02159-7
  3. Kidney Med. 2023 Feb;5(2): 100587
    Caregiver Burden of Autosomal Dominant Polycystic Kidney Disease: A Qualitative Study.
    Dorothee Oberdhan, Andrew C Palsgrove, Jason C Cole, Tess Harris.
       Rationale & Objective: There is limited published research on how autosomal dominant polycystic kidney disease (ADPKD) impacts caregivers. This study explored how caregivers of individuals with ADPKD perceive the burdens placed on them by the disease.
    Study Design: Qualitative study consisting of focus groups and interviews. Discussions were conducted by trained interviewers using semi-structured interview guides.
    Setting & Participants: The research was conducted in 14 countries in North America, South America, Asia, Australia, and Europe. Eligible participants were greater than or equal to 18 years old and caring for a child or adult diagnosed with ADPKD.
    Analytical Approach: The concepts reported were coded using qualitative research software. Data saturation was reached when subsequent discussions introduced no new key concepts.
    Results: Focus groups and interviews were held with 139 participants (mean age, 44.9 years; 66.9% female), including 25 participants who had a diagnosis of ADPKD themselves. Caregivers reported significant impact on their emotional (74.1%) and social life (38.1%), lost work productivity (26.6%), and reduced sleep (25.2%). Caregivers also reported worry about their financial situation (23.7%). In general, similar frequencies of impact were reported among caregivers with ADPKD versus caregivers without ADPKD, with the exception of sleep (8.0% vs 28.9%, respectively), leisure activities (28.0% vs 40.4% respectively), and work/employment (12.0% vs 29.8%, respectively).
    Limitations: The study was observational and designed to elicit concepts, and only descriptive analyses were conducted.
    Conclusions: These findings highlight the unique burden on caregivers in ADPKD, which results in substantial emotional, social, and professional/financial impact.
    Keywords:  Autosomal dominant polycystic kidney disease (ADPKD); burden; caregiver; quality of life
    DOI:  https://doi.org/10.1016/j.xkme.2022.100587
  4. Kidney360. 2023 Jan 27.
    Hypomorphic PKD1 alleles impact disease variability in autosomal dominant polycystic kidney disease.
    Ashima Gulati, Neera K Dahl, Erum A Hartung, Stephanie L Clark, Asha Moudgil, Julie Goodwin, Stefan Somlo.
      
    DOI:  https://doi.org/10.34067/KID.0000000000000064
  5. Am J Case Rep. 2023 Jan 24. 24 e938507
    Predominant Liver Cystic Disease in a New Heterozygotic PKHD1 Variant: A Case Report.
    Jacob D Van Buren, Jeremy T Neuman, Richard Sidlow.
      BACKGROUND The polycystic kidney and hepatic disease 1 (PKHD1) gene codes for fibrocystin-polyductin, a protein that takes part in cell-signaling for cell differentiation, especially in kidney tubules and bile ducts. A homozygous or compound heterozygous defect in this gene can cause autosomal recessive polycystic kidney disease (ARPKD). Polycystic liver disease (PCLD) can also be caused by single heterozygous variants in the PKHD1 gene. ARPKD presents with renal insufficiency and cystic dilatation of bile ducts, although disease is not expected with a single heterozygous mutation. PCLD presents with multiple cysts in the liver and dilated bile ducts as well, but with less of an impact on the kidneys than with ARPKD. Our purpose in publishing this report is to introduce an as-yet unknown variant to the body of genetic defects associated with ARPKD and PCLD, as well as to argue for the likely pathogenicity of the variant according to the prevailing criteria used for classifying gene variants. CASE REPORT We present a patient with a de novo PKHD1 variant currently classified as a variant of unknown significance manifesting with bilaterally enlarged cystic kidneys and echogenic cystic structures in the hepatic portal system, indicative of cystic disease. CONCLUSIONS Given this patient's liver and kidney presentation that does not fully align with either ARPKD or PCLD, the authors believe that the single heterozygous variant in this patient's PKHD1 gene is worthy of reporting. This new single heterozygous variant in PKHD1 gene causing cystic kidney and cystic hepatic disease in the patient should be considered 'likely pathogenic' according to the criteria set by the American College of Medical Genetics.
    DOI:  https://doi.org/10.12659/AJCR.938507
  6. Front Cell Dev Biol. 2022 ;10 937580
    Novel method for the genomic analysis of PKD1 mutation in autosomal dominant polycystic kidney disease.
    Shunlai Shang, Chao Wang, Lang Chen, Wanjun Shen, Yuansheng Xie, Wenge Li, Qinggang Li.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. Although next-generation sequencing (NGS) technology can be used to sequence tens of thousands of DNA molecules simultaneously. It has poor capture efficiency for the six PKD1 pseudogenes and GC-rich regions. Multiplex ligation-dependent probe amplification (MLPA) technology can detect consecutive deletions of exons, but it is less sensitive for single-base mutations. However, pathogenic genes might not be detected in some patients, even when using the above methods. Improving the detection rate of pathogenic genes is an important technical problem hindering clinical diagnosis of ADPKD. Four pedigrees of ADPKD patients with mutation sites not identified by NGS were examined by other methods. First, MLPA was performed. Then, pedigrees in which MLPA did not identify pathogenic genes were subjected to multiplex polymerase chain reaction (MPCR) and targeted region sequencing. Finally, the detected mutation sites were verified by Sanger sequencing. The results showed that MLPA detected the following PKD1 exonic deletion mutations in three pedigrees: PKD1-18 nt-290 nt, PKD1-up-257 nt, PKD1-up-444 nt and PKD1-3 nt-141 nt. A new mutation site was identified through targeted region sequencing in one pedigree: PKD1 NM_001009944: c.151T > C at the protein level, described as p. Cys51Arg. In summary, we established a system of genetic detection and analytical methods, from NGS to MLPA to targeted region sequencing and finally to Sanger sequencing. We combined MPCR and targeted region sequencing for the first time in ADPKD diagnosis, which further improved diagnosis accuracy. Moreover, we identified one new missense mutation and four new deletion mutations.
    Keywords:  ADPKD; MLPA (multiplex ligation-dependent probe amplification); PKD1; mPCR; targeted region sequencing
    DOI:  https://doi.org/10.3389/fcell.2022.937580
  7. JCI Insight. 2023 Jan 24. pii: e155900. [Epub ahead of print]8(2):
    MRAP2 regulates energy homeostasis by promoting primary cilia localization of MC4R.
    Adelaide Bernard, Irene Ojeda Naharros, Xinyu Yue, Francois Mifsud, Abbey Blake, Florence Bourgain-Guglielmetti, Jordi Ciprin, Sumei Zhang, Erin McDaid, Kellan Kim, Maxence V Nachury, Jeremy F Reiter, Christian Vaisse.
      The G protein-coupled receptor melanocortin-4 receptor (MC4R) and its associated protein melanocortin receptor-associated protein 2 (MRAP2) are essential for the regulation of food intake and body weight in humans. MC4R localizes and functions at the neuronal primary cilium, a microtubule-based organelle that senses and relays extracellular signals. Here, we demonstrate that MRAP2 is critical for the weight-regulating function of MC4R neurons and the ciliary localization of MC4R. More generally, our study also reveals that GPCR localization to primary cilia can require specific accessory proteins that may not be present in heterologous cell culture systems. Our findings further demonstrate that targeting of MC4R to neuronal primary cilia is essential for the control of long-term energy homeostasis and suggest that genetic disruption of MC4R ciliary localization may frequently underlie inherited forms of obesity.
    Keywords:  Endocrinology; Melanocortin; Metabolism; Neuroendocrine regulation; Obesity
    DOI:  https://doi.org/10.1172/jci.insight.155900
  8. Dev Cell. 2023 Jan 23. pii: S1534-5807(22)00872-3. [Epub ahead of print]58(2): 139-154.e8
    Primary cilia are WNT-transducing organelles whose biogenesis is controlled by a WNT-PP1 axis.
    Kaiqing Zhang, Fabio Da Silva, Carina Seidl, Michaela Wilsch-Bräuninger, Jessica Herbst, Wieland B Huttner, Christof Niehrs.
      WNT signaling is important in development, stem cell maintenance, and disease. WNT ligands typically signal via receptor activation across the plasma membrane to induce β-catenin-dependent gene activation. Here, we show that in mammalian primary cilia, WNT receptors relay a WNT/GSK3 signal that β-catenin-independently promotes ciliogenesis. Characterization of a LRP6 ciliary targeting sequence and monitoring of acute WNT co-receptor activation (phospho-LRP6) support this conclusion. Ciliary WNT signaling inhibits protein phosphatase 1 (PP1) activity, a negative regulator of ciliogenesis, by preventing GSK3-mediated phosphorylation of the PP1 regulatory inhibitor subunit PPP1R2. Concordantly, deficiency of WNT/GSK3 signaling by depletion of cyclin Y and cyclin-Y-like protein 1 induces primary cilia defects in mouse embryonic neuronal precursors, kidney proximal tubules, and adult mice preadipocytes.
    Keywords:  GSK3; LRP6; PP1; Wnt; cilia; exencephaly; lipodystrophy
    DOI:  https://doi.org/10.1016/j.devcel.2022.12.006
  9. Front Cell Dev Biol. 2022 ;10 1092161
    Ciliary signaling proteins are mislocalized in the brains of Bardet-Biedl syndrome 1-null mice.
    Toneisha Stubbs, James I Bingman, Jason Besse, Kirk Mykytyn.
      In the brain, primary cilia are found on most, if not all, central neurons. The importance of neuronal cilia is underscored by the fact that human diseases caused by primary cilia dysfunction, which are known as ciliopathies, are associated with neuropathologies, including neuropsychiatric disorders and learning and memory deficits. Neuronal cilia are enriched for certain G protein-coupled receptors and their downstream effectors, suggesting they sense and respond to neuromodulators in the extracellular milieu. GPCR ciliary localization is disrupted in neurons from mouse models of the ciliopathy Bardet-Biedl syndrome, with GPCRs failing to localize to cilia, indicating the Bardet-Biedl syndrome proteins are required for trafficking of G protein-coupled receptors into neuronal cilia. Yet, dopamine receptor 1 accumulates in cilia in the absence of Bardet-Biedl syndrome proteins, suggesting Bardet-Biedl syndrome proteins are required for normal ciliary import and export. To further explore the roles of the Bardet-Biedl syndrome proteins in neuronal cilia, we examined localization of ciliary signaling proteins in a new constitutive Bbs1 knockout mouse model. Interestingly, we find that two additional ciliary G protein-coupled receptors (Gpr161 and Gpr19) abnormally accumulate in cilia on Bardet-Biedl syndrome neurons. In addition, we find that the GPCR signaling protein β-arrestin accumulates in a subset of cilia in the brain, suggesting the presence of additional unidentified ciliary G protein-coupled receptors. These results confirm the importance of the Bardet-Biedl syndrome proteins in establishing ciliary GPCR pathways and indicate that loss of Bbs1 leads to complex changes in the localization of signaling proteins in the brain.
    Keywords:  Bardet-Biedl syndrome; GPR19; Gpr161; beta arrestin; cilia; ciliopathy
    DOI:  https://doi.org/10.3389/fcell.2022.1092161
  10. Stem Cells Int. 2023 ;2023 6494486
    Characterization of Primary Cilia Formation in Human ESC-Derived Retinal Organoids.
    Ke Ning, Ziming Luo, Tia J Kowal, Matthew Tran, Rishab Majumder, Trent M Jarin, Albert Y Wu, Jeffrey L Goldberg, Yang Sun.
       Objectives: Primary cilia are conserved organelles found in polarized mammalian cells that regulate neuronal growth, migration, and differentiation. Proper cilia formation is essential during eye development. Our previous reports found that both amacrine and retinal ganglion cells (RGCs) contain primary cilia in primate and rodent retinas. However, whether primary cilia are present in the inner retina of human retinal organoids remains unknown. The purpose of this study is to characterize the primary cilia distribution in human embryonic stem cell (hESC-derived retinal organoid development.
    Materials and Methods: Retinal organoids were differentiated from a hESC line, harvested at various developmental timepoints (day 44-day 266), and immunostained with antibodies for primary cilia, including Arl13b (for the axoneme), AC3, and Centrin3 (for the basal body). AP2α, Prox1, GAD67, Calretinin, GFAP, PKCα, and Chx10 antibodies as well as Brn3b-promoted tdTomato expression were used to visualize retinal cell types.
    Results: A group of ciliated cells were present in the inner aspects of retinal organoids from day 44 to day 266 in culture. Ciliated Chx10-positive retinal progenitor cells, GFAP-positive astrocytes, and PKCα-positive rod-bipolar cells were detected later during development (day 176 to day 266). Ciliation persisted during all stages of retinal developmental in AP2α-positive amacrine cells, but it was decreased in Brn3b-positive retinal ganglion cells (RGCs) at later time points. Additionally, AC3-positive astrocytes significantly decreased during the later stages of organoid formation.
    Conclusions: Amacrine cells in retinal organoids retain cilia throughout development, whereas RGC ciliation gradually and progressively decreases with organoid maturation.
    DOI:  https://doi.org/10.1155/2023/6494486
  11. Kidney Int. 2023 Feb;pii: S0085-2538(22)00975-9. [Epub ahead of print]103(2): 429
    Corrigendum to "Ttc21b deficiency attenuates autosomal dominant polycystic kidney disease in a kidney tubular- and maturation-dependent manner." Kidney Int. 2022;102:577-591.
    Wei Wang, Luciane M Silva, Henry H Wang, Matthew A Kavanaugh, Tana S Pottorf, Bailey A Allard, Damon T Jacobs, Rouchen Dong, Joseph T Cornelius, Aakriti Chaturvedi, Katherine I Swenson-Fields, Timothy A Fields, Michele T Pritchard, Madhulika Sharma, Chad Slawson, Darren P Wallace, James P Calvet, Pamela V Tran.
      
    DOI:  https://doi.org/10.1016/j.kint.2022.11.015
  12. Pathobiology. 2023 Jan 25.
    Renal cell carcinoma in end-stage renal disease: A retrospective study in patients from Hungary.
    Dávid Semjén, Borbála Dénes, Áron Somorácz, Attila Fintha, Gertrúd Forika, Alex Jenei, Deján Dobi, Tamás Micsik, Kornélia Veronika Eizler, Nándor Giba, Fanni Sánta, Anita Sejben, Béla Iványi, Levente Kuthi.
       INTRODUCTION: End-stage renal disease (ESRD) and acquired cystic kidney disease (ACKD) are known risk factors for renal cell carcinoma (RCC). Hereby, the clinicopathological features of RCCs developed in ESRD were investigated.
    METHODS: A database consisting of 34 tumors from 31 patients with ESRD among 2 566 nephrectomy samples of RCC was built. The demographic, clinical, and follow-up data along with pathological parameters were analyzed. The RCCs were diagnosed according to the current WHO Classification of Urinary and Male Genital Tumors.
    RESULTS: Twenty-two tumors developed in men and 12 in women, with a median age of 56 years (range: 27-75 years). The causes of ESRD were glomerulonephritis (n=7), hypertensive kidney disease (n=6), autosomal dominant polycystic kidney disease (n=6), chronic pyelonephritis (n=4), diabetic nephropathy (n=3), chemotherapy-induced nephropathy (n=1), and undetermined (n=4). ACKD complicated ESRD in 12 patients. The following histological subtypes were identified: clear cell RCC (n=19), papillary RCC (n=5), clear cell papillary tumor (n=5), ACKD RCC (n=3), and eosinophilic solid and cystic RCC (n=2). The median tumor size was 31 mm (range: 10-80 mm), and 32 tumors were confined to the kidney (pT1-pT2). There was no tumor-specific death during the period of this study. Progression was registered in one patient.
    CONCLUSION: In our cohort, the most common RCC subtype was clear cell RCC (55%), with a frequency that exceeded international data appreciably (14-25%). The incidence of clear cell papillary tumor and ACKD RCC (14.7% and 8.5%) was lower than data reported in the literature (30% and 40%). Our results indicate a favorable prognosis of RCC in ESRD.
    DOI:  https://doi.org/10.1159/000529276
  13. Commun Biol. 2023 Jan 23. 6(1): 91
    Building train carriages for ciliary transport: (IFT-)A complex task.
    Francisco Gonçalves-Santos, Maria J G De-Castro, Ana R G De-Castro, Tiago J Dantas.
      
    DOI:  https://doi.org/10.1038/s42003-023-04426-9
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