bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022–10–02
eleven papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Preventive project of Autosomal Dominant Polycystic Kidney Disease (ADPKD).
  2. Cilia regeneration requires an RNA splicing factor from the ciliary base.
  3. Design and Basic Characteristics of a National Patient-Powered Registry in ADPKD.
  4. The importance of the number of antihypertensives in the progression of autosomal dominant polycystic kidney disease.
  5. Should all patients with polycystic kidney disease be screened for intracraneal aneurysms?
  6. Targeting the LPA1 signalling pathway for fibrosis therapy: a patent review (2010-present).
  7. Microtubule modification defects underlie cilium degeneration in cell models of retinitis pigmentosa associated with pre-mRNA splicing factor mutations.
  8. Intraflagellar transport protein 88 interacts with polycystin 2 to regulate mechanosensitive hedgehog signaling in mandibular condylar chondrocytes.
  9. Primary Ciliary Dyskinesia: Phenotype Resulting From a Novel Variant of LRRC56 Gene.
  10. CCNO mutation as a cause of primary ciliary dyskinesia: A case report.
  11. Bicaudal-C Post-transcriptional regulator of cell fates and functions.
  1. Nefrologia (Engl Ed). 2021 Nov-Dec;41(6):pii: S2013-2514(21)00133-4. [Epub ahead of print]41(6): 704-706
    Preventive project of Autosomal Dominant Polycystic Kidney Disease (ADPKD).
    Rafael J Esteban de la Rosa, Antonio Miguel Poyatos Andújar, Ana Isabel Morales García, Luis Martínez Navarro, María García Valverde, Juan Antonio Bravo Soto.
      
    DOI:  https://doi.org/10.1016/j.nefroe.2021.12.006
  2. Cell Regen. 2022 Oct 01. 11(1): 29
    Cilia regeneration requires an RNA splicing factor from the ciliary base.
    Kaiming Xu, Guangshuo Ou.
      Cilia are microtubule-based organelles projected from most eukaryotic cell surfaces performing cell motility and signaling. Several previously recognized non-ciliary proteins play crucial roles in cilium formation and function. Here, we provide additional evidence that the Caenorhabditis elegans RNA splicing factor PRP-8/PRPF8 regulates ciliogenesis and regeneration from the ciliary base. Live imaging of GFP knock-in animals reveals that the endogenous PRP-8 localizes in the nuclei and the ciliary base. A weak loss-of-function allele of prp-8 affects ciliary structure but with little impact on RNA splicing. Conditional degradation of PRP-8 within ciliated sensory neurons showed its direct and specific roles in cilium formation. Notably, the penetrance of ciliary defects correlates with the reduction of PRP-8 at the ciliary base but not nuclei, and sensory neurons regenerated cilia accompanying PRP-8 recovery from the ciliary base rather than the nuclei. We suggest that PRP-8 at the ciliary base contributes to cilium formation and regeneration.
    Keywords:  Ciliogenesis; Cilium regeneration; PRP-8/PRPF8; RNA splicing factor
    DOI:  https://doi.org/10.1186/s13619-022-00130-x
  3. Kidney360. 2022 Aug 25. 3(8): 1350-1358
    Design and Basic Characteristics of a National Patient-Powered Registry in ADPKD.
    Elise Hoover, Ronald D Perrone, Chris Rusconi, Beverly Benson, Neera K Dahl, Berenice Gitomer, Amy Manelli, Michal Mrug, Meyeon Park, Stephen L Seliger, Milind A Phadnis, Nadeesha Thewarapperuma, Terry J Watnick.
       Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease worldwide. Over the past five years, the therapeutic pipeline for ADPKD has expanded, leading to a growing need for patient enrollment in clinical trials and improved understanding of patient-centered outcomes that can be used in trial design. To advance these goals, the Polycystic Kidney Disease Foundation (PKDF) established a national web-based ADPKD Registry.
    Methods: The ADPKD Registry is hosted on a secure, HIPAA-compliant, online platform (IQVIA, oc-meridian.com/pkdcure). Participants are consented through the online system and complete a series of modules. The Core Questionnaire includes patient-reported diagnosis, latest creatinine values, and comorbidities. Additional modules include surveys of family history, diet, quality of life, extrarenal manifestations, and attitudes surrounding research participation.
    Results: As of October 2021, 1563 ADPKD patients across the United States have registered and completed the Core Questionnaire. Participants have a median age of 44 years and are 72% women, 93% White, with 4% self-identifying as Hispanic/Latino and 2% as Black. All CKD stages are present, including post kidney transplant. To date, seven clinical studies have used the Registry as a recruitment tool. Additionally, quality-of-life burden scores revealed a correlation with disease stage as determined by kidney function.
    Conclusions: The Registry described here is the only one of its kind and is a valuable longitudinal research tool encompassing all stages of ADPKD. The registry will allow investigators to pursue a range of research questions related to the management of ADPKD, including definition of health-related quality of life (HRQoL) outcomes and recruitment for a variety of observational and therapeutic clinical protocols.
    Keywords:  ADPKD; cystic kidney disease; kidney disease; outcomes; polycystic kidney disease; quality of life; registries
    DOI:  https://doi.org/10.34067/KID.0002372022
  4. Nefrologia (Engl Ed). 2021 May-Jun;41(3):pii: S2013-2514(21)00062-6. [Epub ahead of print]41(3): 362-364
    The importance of the number of antihypertensives in the progression of autosomal dominant polycystic kidney disease.
    Víctor Martínez Jiménez, Ana Noelia Hernández González, Inmaculada López Jiménez, Lidya Rodríguez Peña, Liliana Galbis Martínez, Manuel Santa-Olalla González, Guadalupe Ruiz Merino, Encarna Guillén Navarro.
      
    DOI:  https://doi.org/10.1016/j.nefroe.2021.07.002
  5. Nefrologia (Engl Ed). 2021 Nov-Dec;41(6):pii: S2013-2514(21)00132-2. [Epub ahead of print]41(6): 702-703
    Should all patients with polycystic kidney disease be screened for intracraneal aneurysms?
    Covadonga López Del Moral Cuesta, Jaime Mazón Ruiz, Gema Fernández Fresnedo.
      
    DOI:  https://doi.org/10.1016/j.nefroe.2021.12.005
  6. Expert Opin Ther Pat. 2022 Sep 29.
    Targeting the LPA1 signalling pathway for fibrosis therapy: a patent review (2010-present).
    Zhihao Gu, Yong Yan, Hequan Yao, Kejiang Lin, Xuanyi Li.
       INTRODUCTION: Fibrosis is a disease that damages organs and even causes death. Because of the complicated pathogenesis, the development of drugs for fibrosis is challenging. In the lysophosphatidic acid receptor type 1 (LPA1) signalling pathway, LPA1 and its downstream Rho-associated coiled-coil forming protein kinase (ROCK) are related to the process of fibrosis. Targeting LPA1 signalling pathway is a potential strategy for the treatment of fibrosis.
    AREA COVERED: This review describes the process of fibrosis mediated by the LPA1 signalling pathway and then summarizes LPA1 antagonist patents reported since 2010 and ROCK inhibitor patents since 2017 according to their scaffolds based on the Cortellis Drug Discovery Intelligence database. Information on LPA1 antagonists entering clinical trials is integrated.
    EXPERT OPINION: Over the past decade, a large number of antagonists targeting the LPA1 signalling pathway have been patented for fibrosis therapy. A limited number of compounds have entered clinical trials. Different companies and research groups have used different scaffolds when designing compounds for fibrosis therapy. Therefore, LPA1 and ROCK are competitive targets for the development of new therapies for fibrosis to provide a potential treatment method for fibrosis in the future.
    Keywords:  LPA1 antagonists; LPA1 signalling pathway; ROCK inhibitors; fibrosis; patent review
    DOI:  https://doi.org/10.1080/13543776.2022.2130753
  7. Front Genet. 2022 ;13 1009430
    Microtubule modification defects underlie cilium degeneration in cell models of retinitis pigmentosa associated with pre-mRNA splicing factor mutations.
    Liliya Nazlamova, Suly Saray Villa Vasquez, Jenny Lord, Varshini Karthik, Man-Kim Cheung, Jörn Lakowski, Gabrielle Wheway.
      Retinitis pigmentosa (RP) is the most common cause of hereditary blindness, and may occur in isolation as a non-syndromic condition or alongside other features in a syndromic presentation. Biallelic or monoallelic mutations in one of eight genes encoding pre-mRNA splicing factors are associated with non-syndromic RP. The molecular mechanism of disease remains incompletely understood, limiting opportunities for targeted treatment. Here we use CRISPR and base edited PRPF6 and PRPF31 mutant cell lines, and publicly-available data from human PRPF31 +/- patient derived retinal organoids and PRPF31 siRNA-treated organotypic retinal cultures to confirm an enrichment of differential splicing of microtubule, centrosomal, cilium and DNA damage response pathway genes in these cells. We show that genes with microtubule/centrosome/centriole/cilium gene ontology terms are enriched for weak 3' and 5' splice sites, and that subtle defects in spliceosome activity predominantly affect efficiency of splicing of these exons. We suggest that the primary defect in PRPF6 or PRPF31 mutant cells is microtubule and centrosomal defects, leading to defects in cilium and mitotic spindle stability, with the latter leading to DNA damage, triggering differential splicing of DNA damage response genes to activate this pathway. Finally, we expand understanding of "splicing factor RP" by investigating the function of TTLL3, one of the most statistically differentially expressed genes in PRPF6 and PRPF31 mutant cells. We identify that TTLL3 is the only tubulin glycylase expressed in the human retina, essential for monoglycylation of microtubules of the cilium, including the retinal photoreceptor cilium, to prevent cilium degeneration and retinal degeneration. Our preliminary data suggest that rescue of tubulin glycylation through overexpression of TTLL3 is sufficient to rescue cilium number in PRPF6 and PRPF31 mutant cells, suggesting that this defect underlies the cellular defect and may represent a potential target for therapeutic intervention in this group of disorders.
    Keywords:  cilia; ciliopathies; photoreceptor; pre-mRNA splicing; retinitis pigmentosa
    DOI:  https://doi.org/10.3389/fgene.2022.1009430
  8. Arch Oral Biol. 2022 Sep 19. pii: S0003-9969(22)00205-9. [Epub ahead of print]143 105548
    Intraflagellar transport protein 88 interacts with polycystin 2 to regulate mechanosensitive hedgehog signaling in mandibular condylar chondrocytes.
    Zhuo Wang, Guoliang Sa, Liwu Zheng, Zequan Wei, Zhuoyu Zhang, Yanping Hu, Xuewen Yang.
       OBJECTIVE: This study aimed to explore whether intraflagellar transport protein 88 (IFT88) was associated with polycystin 2 during mechanotransduction of mandibular condylar chondrocytes.
    METHODS: Rat mandibular condylar chondrocytes isolated from the condylar bone-cartilage junction were subjected to cyclic tensile strain (0.1 Hz, 10% elongation). Overexpression of IFT88 was achieved by lentiviral vector-mediated transfection. Knockdown of IFT88 and polycystin 2 was achieved by small interfering RNA (siRNA). The prevalence and length of cilia were reflected by immunofluorescence staining. The activities of hedgehog signaling were evaluated by western blot analysis. The interaction between polycystin 2 and IFT88 was evaluated by conducting a co-immunoprecipitation (co-IP) assay.
    RESULTS: Overexpression of IFT88 increased the length of cilia. Protein levels of polycystin 2, Indian hedgehog (Ihh), Patched 1 (Ptch1), Smoothened (Smo), and Glioma-associated oncogene homolog 1 (Gli1) were elevated in IFT88-overexpressing mandibular condylar chondrocytes under cyclic tensile strain. Knockdown of the protein level of IFT88 reduced the prevalence and length of cilia, and protein levels of polycystin 2, Ihh, Ptch1, Smo, and Gli1. A co-IP assay showed that IFT88 formed a complex with polycystin 2 under cyclic tensile strain. Knockdown of polycystin 2 decreased the protein levels of IFT88, Ihh, Ptch1, Smo, and Gli1 in mandibular condylar chondrocytes following cyclic tensile strain.
    CONCLUSION: These findings highlight the vital role of an interaction between IFT88 and polycystin 2 in mechanosensitive hedgehog signaling in mandibular condylar chondrocytes following cyclic tensile strain, which suggest that therapies regulating polycystin 2 may be considered for the disorders of temporomandibular joints.
    Keywords:  Hedgehog signaling; Intraflagellar transport protein 88; Mandibular condylar chondrocytes; Mechanotransduction; Polycystin 2; Primary cilia
    DOI:  https://doi.org/10.1016/j.archoralbio.2022.105548
  9. Cureus. 2022 Aug;14(8): e28472
    Primary Ciliary Dyskinesia: Phenotype Resulting From a Novel Variant of LRRC56 Gene.
    Badriah G Alasmari, Muhammad Saeed, Mohammed A Alomari, Mohammad Alsumaili, Ali M Tahir.
      Primary ciliary dyskinesia (PCD) involves cilia impairment, with resultant symptoms of repeated respiratory infections, sinusitis, and infertility. We report a seven-year-old boy of Arab ethnicity, with consanguineous parents, who was identified to have situs inversus totalis in neonatal life. There was a significant family history of ciliopathy as situs inversus totalis, infertility, and recurrent respiratory infections were noted in his two paternal uncles. From five months of age, the child started to have recurrent hospital visits due to respiratory infections. Infancy was marked by failure to thrive along with delay in achieving developmental milestones. Next-generation sequencing of known or potential ciliopathy genes revealed him homozygous for a novel mutation c.494T>C of the LRRC56 gene, thus defining PCD as a potential cause of his features.
    Keywords:  a new variant; lrrc56; lrrc56 gene; paediatrics respiratory infection; primary ciliary dyskinesia; primary ciliary dyskinesia (pcd); respiratory infection; situs inversus totalis
    DOI:  https://doi.org/10.7759/cureus.28472
  10. World J Clin Cases. 2022 Sep 06. 10(25): 9148-9155
    CCNO mutation as a cause of primary ciliary dyskinesia: A case report.
    Yun-Yan Zhang, Yan Lou, Han Yan, Hao Tang.
       BACKGROUND: Primary ciliary dyskinesia (PCD) is an uncommon and genetically diverse condition. According to reports, most patients had more than 50 visits before being diagnosed with PCD, and the age at diagnosis was mostly in preschool, with an average age of about (10.9 ± 14.4) years old. CCNO is a pathogenic gene that regulates the cell cycle, and its mutation is linked to the uncommon human genetic disorder PCD. Although the prevalence of the CCNO mutation is regarded to be exceptionally low, new reports of this mutation have increased in comparison to prior ones. PCD patients with CCNO are rare, and the incidence rate is no more than 2% in whole PCD patients.
    CASE SUMMARY: Here, we report a case of a young Chinese woman diagnosed with PCD, who was found to carry the CCNO gene by whole exon gene sequencing. In this case, a young non-smoking Chinese female exhibiting recurrent cough and sputum at birth. Chest computed tomography (CT) showed bronchiectasis with infection, and sinus CT showed chronic sinusitis. However, the patient had no visceral transposition and no history of infertility. Under electron microscope, it was found that cilia were short and reduced in number, and no power arm of cilia was observed. Whole exon sequencing analysis of the genome of the patient showed that the patient carried CCNO pathogenic gene, exon c.303C>A nonsense mutation and c.248_252dup frameshift mutation. Her clinical symptoms and CT images were improved after two months of treatment with aerosol inhalation and oral azithromycin.
    CONCLUSION: The results showed that CCNO is an important cause of PCD. More mutant genes that may contribute to genetically diverse disorders like PCD have been discovered as sequencing technology has advanced. Furthermore, the increase of genetic information makes it easier to diagnose uncommon diseases in clinical practice.
    Keywords:  CCNO gene; Case report; Clinical profiles; Primary ciliary immobility disorder; Review of literature; Whole exon gene sequencing
    DOI:  https://doi.org/10.12998/wjcc.v10.i25.9148
  11. Front Cell Dev Biol. 2022 ;10 981696
    Bicaudal-C Post-transcriptional regulator of cell fates and functions.
    Megan E Dowdle, Charlotte R Kanzler, Cole R K Harder, Samuel Moffet, Maya N Walker, Michael D Sheets.
      Bicaudal-C (Bicc1) is an evolutionarily conserved RNA binding protein that functions in a regulatory capacity in a variety of contexts. It was originally identified as a genetic locus in Drosophila that when disrupted resulted in radical changes in early development. In the most extreme phenotypes embryos carrying mutations developed with mirror image duplications of posterior structures and it was this striking phenotype that was responsible for the name Bicaudal. These seminal studies established Bicc1 as an important regulator of Drosophila development. What was not anticipated from the early work, but was revealed subsequently in many different organisms was the broad fundamental impact that Bicc1 proteins have on developmental biology; from regulating cell fates in vertebrate embryos to defects associated with several human disease states. In the following review we present a perspective of Bicc1 focusing primarily on the molecular aspects of its RNA metabolism functions in vertebrate embryos.
    Keywords:  Bicaudal-C family RNA binding protein 1 (Bicc1); cell fate and differentiation; embryonic cell fate; mRNA translation; post-transcripional control
    DOI:  https://doi.org/10.3389/fcell.2022.981696
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