bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023‒03‒05
sixteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. The effect of autosomal dominant polycystic kidney disease on mucociliary clearance.
  2. Defining the Specialized Functions of cAMP Signals in an Organelle Formerly Deemed to Have No Function: The Primary Cilium.
  3. Life-Threatening Retroperitoneal Hemorrhage Following Cyst Rupture in Autosomal Dominant Polycystic Kidney Disease (ADPKD): A Case Report.
  4. The Ciliary Lumen Accommodates Passive Diffusion and Vesicle-Assisted Trafficking in Cytoplasm-Ciliary Transport.
  5. IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans.
  6. Elevated checkpoint inhibitor expression and Treg cell number in autosomal dominant polycystic kidney disease and their correlation with disease parameters and hypertension.
  7. Physiological Condition Dependent Changes in Ciliary GPCR Localization in the Brain.
  8. IHH, SHH, and primary cilia mediate epithelial-stromal cross-talk during decidualization in mice.
  9. Compound heterozygosity of a de novo submicroscopic deletion and an inherited frameshift pathogenic variant in the PKHD1 gene in a fetus with bilaterally enlarged and echogenic kidneys, enlarged abdomen and oligohydramnios.
  10. Cytoskeleton: The many flavors of cilia transition fibers.
  11. Y-27632 Impairs Angiogenesis on Extra-Embryonic Vasculature in Post-Gastrulation Chick Embryos.
  12. RABL4/IFT27 in a nucleotide-independent manner promotes phospholipase D ciliary retrieval via facilitating BBSome reassembly at the ciliary tip.
  13. MAP9/MAPH-9 supports axonemal microtubule doublets and modulates motor movement.
  14. Cilia Ultrastructure Associated with Primary Ciliary Dyskinesia in Omani Patients.
  15. Characterization of a DRC1 null variant associated with primary ciliary dyskinesia and female infertility.
  16. CEP162 deficiency causes human retinal degeneration and reveals a dual role in ciliogenesis and neurogenesis.
  1. Eur Arch Otorhinolaryngol. 2023 Feb 28.
    The effect of autosomal dominant polycystic kidney disease on mucociliary clearance.
    İrfan Kara, İlyas Öztürk, Adem Doğaner, Muhammed Gazi Yıldız, Fatma Betül Güzel, Ahmet Kılıç, İsrafil Orhan, Orçun Altınören.
      PURPOSE: Autosomal dominant polycystic kidney disease (ADPKD) is a renal disease with genetic transmisson. Mutations in the PKD1 and PKD2 genes, which encode integral membrane proteins of the cilia of primary renal tubule epithelial cells, are seen in ADPKD. The aim of this study was to evaluate the sinonasal epithelium, which is epithelium with cilia, by measuring the nasal mucociliary clearance time, and to investigate the effect of ADPKD on nasal mucociliary clearance.METHODS: The study included 34 patients, selected from patients followed up in the Nephrology Clinic, and 34 age and gender-matched control group subjects. The nasal mucociliary clearance time (NMCT) was measured with the saccharin test.
    RESULTS: The mean age of the study subjects was 47.15 ± 14.16 years in the patient group and 47.65 ± 13.85 years in the control group. The eGFR rate was determined as mean 72.06 ± 34.26 mL/min in the patient group and 99.79 ± 17.22 mL/min in the control group (p < 0.001). The NMCT was determined to be statistically significantly longer in the patient group (903.6 ± 487.8 s) than in the control group (580 ± 259 s) (p = 0.006).
    CONCLUSIONS: The study results showed that the NMCT was statistically significantly longer in patients with ADPKD compared to the control group, but in the linear regression analysis results, no correlation was determined between eGFR and NMCT.
    Keywords:  Autosomal dominant polycystic kidney disease; Genetic disease; Nasal mucociliary clearance; Saccharin test
    DOI:  https://doi.org/10.1007/s00405-023-07891-4
  2. Function (Oxf). 2023 ;4(2): zqad007
    Defining the Specialized Functions of cAMP Signals in an Organelle Formerly Deemed to Have No Function: The Primary Cilium.
    Aldebaran M Hofer.
      
    Keywords:  cyclic AMP signaling; hedgehog signaling; kidney cysts; phosphodiesterases; primary cilia
    DOI:  https://doi.org/10.1093/function/zqad007
  3. Am J Case Rep. 2023 Feb 27. 24 e938889
    Life-Threatening Retroperitoneal Hemorrhage Following Cyst Rupture in Autosomal Dominant Polycystic Kidney Disease (ADPKD): A Case Report.
    Parikshit Duriseti, Yeshwanter Radhakrishnan, Maroun Chedid, Christian Hanna, Theodora A Potrezke, Fouad T Chebib.
      BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of kidney failure worldwide. It is characterized by cyst formation and growth, kidney parenchymal destruction, and complications including cyst infection, nephrolithiasis, cyst rupture, and cyst hemorrhage. Cyst bleeding is typically a self-limited event. This case report describes a 60-year-old man with ADPKD admitted with retroperitoneal hemorrhage following renal cyst rupture requiring embolization of a bleeding left lumbar artery and use of tranexamic acid. CASE REPORT A 60-year-old man with ADPKD presented with altered mental status. Labs noted hemoglobin of 4.7 g/dL. Abdominal imaging revealed polycystic kidneys and large left retroperitoneal hematoma. Angiogram demonstrated active bleeding from left L3 lumbar artery which was embolized. He was admitted to intensive care unit for hemorrhagic shock requiring multiple blood transfusions. Hemoglobin continued to downtrend despite blood products with repeat imaging demonstrating expanding retroperitoneal bleed. He underwent repeat angiogram and though there was no active bleeding, prophylactic embolization of left L1, L3, L4 lumbar and left renal capsular arteries were performed. Hemoglobin stabilized for next 3 days but continued to downtrend subsequently. Oral tranexamic acid was trialed with stabilization of the hemoglobin. CONCLUSIONS Life-threatening retroperitoneal hemorrhage following cyst rupture in the absence of major trauma or use of anti-coagulants, is a rare complication in ADPKD. Treatment involves resuscitation with blood products, management of shock, and interventional radiology-guided embolization. Tranexamic acid may be considered when the above measures fail. Nephrectomy may be indicated for refractory bleeding. This report highlights the diagnosis and management of massive cyst bleeding in ADPKD.
    DOI:  https://doi.org/10.12659/AJCR.938889
  4. Mol Biol Cell. 2023 Mar 01. mbcE22100452
    The Ciliary Lumen Accommodates Passive Diffusion and Vesicle-Assisted Trafficking in Cytoplasm-Ciliary Transport.
    Andrew Ruba, Mark Tingey, Wangxi Luo, Jingjie Yu, Athanasios Evangelou, Rachel Higgins, Saovleak Khim, Weidong Yang.
      Transport of membrane and cytosolic proteins into the primary cilium is essential for its role in cellular signaling. Using a virtual 3D super-resolution light microscopy, the movements of membrane and soluble proteins from the cytoplasm to the primary cilium was mapped. In addition to the well-characterized intraflagellar transport (IFT) route, we found two new pathways within the lumen of the primary cilium were identified. Specifically, passive diffusion and vesicle-assisted transport routes that, are adopted by proteins for cytoplasm-cilium transport in live cells. Through these pathways, approximately half of IFT motors (KIF3A) and cargo (α-tubulin) take the passive diffusion route, and more than half of membrane-embedded G protein coupled receptors (SSTR3 and HTR6) use RAB8A-regulated vesicles to transport into and inside primary cilia. Furthermore, ciliary lumen transport is the preferred route for membrane proteins in the early stages of ciliogenesis and inhibition of SSTR3 vesicle transport completely blocks ciliogenesis. Furthermore, clathrin-mediated, signal-dependent internalization of SSTR3 also occurs through the ciliary lumen. These transport routes were also observed in Chlamydomonas reinhardtii flagella, suggesting their conserved roles in trafficking of ciliary proteins. [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E22-10-0452
  5. medRxiv. 2023 Feb 26. pii: 2023.02.23.23286106. [Epub ahead of print]
    IFT74 variants cause skeletal ciliopathy and motile cilia defects in mice and humans.
    Zeineb Bakey, Oscar A Cabrera, Julia Hoefele, Dinu Antony, Kaman Wu, Michael W Stuck, Dimitra Micha, Thibaut Eguether, Abigail O Smith, Nicole N van der Wel, Matias Wagner, Lara Strittmatter, Philip L Beales, Julie A Jonassen, Isabelle Thiffault, Maxime Cadieux-Dion, Laura Boyes, Saba Sharif, Beyhan Tüysüz, Desiree Dunstheimer, Hans W M Niessen, William Devine, Cecilia W Lo, Hannah M Mitchison, Miriam Schmidts, Gregory J Pazour.
      Motile and non-motile cilia are critical to mammalian development and health. Assembly of these organelles depends on proteins synthesized in the cell body and transported into the cilium by intraflagellar transport (IFT). A series of human and mouse IFT74 variants were studied to understand the function of this IFT subunit. Humans missing exon 2, which codes for the first 40 residues, presented an unusual combination of ciliary chondrodysplasia and mucociliary clearance disorders while individuals carrying biallelic splice site variants developed a lethal skeletal chondrodysplasia. In mice, variants thought to remove all Ift74 function, completely block ciliary assembly and result in midgestational lethality. A mouse allele that removes the first 40 amino acids, analogous to the human exon 2 deletion, results in a motile cilia phenotype with mild skeletal abnormalities. In vitro studies suggest that the first 40 amino acids of IFT74 are dispensable for binding of other IFT subunits but are important for tubulin binding. Higher demands on tubulin transport in motile cilia compared to primary cilia could account for the motile cilia phenotype observed in human and mice.
    DOI:  https://doi.org/10.1101/2023.02.23.23286106
  6. Clin Exp Med. 2023 Mar 04.
    Elevated checkpoint inhibitor expression and Treg cell number in autosomal dominant polycystic kidney disease and their correlation with disease parameters and hypertension.
    Ali Sahin, Ismail Kocyigit, Kubra Aslan, Eray Eroglu, Alparslan Demiray, Ahmet Eken.
      Autosomal dominant polycystic kidney disease (ADPKD) has cancer-like pathophysiology. In this study, we aimed to investigate the phenotype of peripheral blood (PB) T cell subsets and immune checkpoint inhibitor expression of ADPKD patients across different chronic kidney disease (CKD) stages. Seventy-two patients with ADPKD and twenty-three healthy controls were included in the study. The patients were grouped into five different CKD stages, according to glomerular filtration rate (GFR). PB mononuclear cells were isolated and T cell subsets and cytokine production were examined by flow cytometry. CRP levels, height-adjusted total kidney volume (htTKV), rate of hypertension (HT) differed significantly across different GFR stages in ADPKD. T cell phenotyping revealed significantly elevated CD3+ T cells, CD4+, CD8+, double-negative, and double-positive subsets and significantly elevated IFN-γ and TNF-α producing subsets of CD4+, CD8+ cells. The expression of checkpoint inhibitors CTLA-4, PD-1, and TIGIT by T cell subsets was also increased to various extent. Additionally, Treg cell numbers and suppressive markers CTLA-4, PD-1, and TIGIT were significantly elevated in ADPKD patients' PB. Treg CTLA4 expression and CD4CD8DP T cell frequency in patients with HT were significantly higher. Lastly, HT and increased htTKV and higher frequency of PD1+ CD8SP were found to be risk factors for rapid disease progression. Our data provide the first detailed analyses of checkpoint inhibitor expression by PB T cell subsets during stages of ADPKD, and that a higher frequency of PD1+ CD8SP cells is associated with rapid disease progression.
    Keywords:  Autosomal dominant polycystic kidney disease; Checkpoint inhibitors; Hypertension; T cell subsets
    DOI:  https://doi.org/10.1007/s10238-023-01031-2
  7. eNeuro. 2023 Feb 27. pii: ENEURO.0360-22.2023. [Epub ahead of print]
    Physiological Condition Dependent Changes in Ciliary GPCR Localization in the Brain.
    Kathryn M Brewer, Staci E Engle, Ruchi Bansal, Katlyn K Brewer, Kalene R Jasso, Jeremy C McIntyre, Christian Vaisse, Jeremy F Reiter, Nicolas F Berbari.
      Primary cilia are cellular appendages critical for diverse types of singling. They are found on most cell types, including cells throughout the central nervous system. Cilia preferentially localize certain G protein-coupled receptors (GPCRs) and are critical for mediating the signaling of these receptors. Several of these neuronal GPCRs have recognized roles in feeding behavior and energy homeostasis. Cell and model systems like C. elegans and Chlamydomonas have implicated both dynamic GPCR cilia localization and cilia length and shape changes as key for signaling. It is unclear if mammalian ciliary GPCRs utilize similar mechanisms in vivo and under what conditions these processes may occur. Here, we assess two neuronal cilia GPCRs, melanin-concentrating hormone receptor 1 (MCHR1) and neuropeptide-Y receptor 2 (NPY2R), as mammalian model ciliary receptors in the mouse brain. We test the hypothesis that dynamic localization to cilia occurs under physiological conditions associated with these GPCRs' functions. Both receptors are involved in feeding behaviors, and MCHR1 is also associated with sleep and reward. Cilia were analyzed with a computer-assisted approach allowing for unbiased and high throughput analysis. We measured cilia frequency, length, and receptor occupancy. We observed changes in ciliary length, receptor occupancy, and cilia frequency under different conditions for one receptor but not another and in specific brain regions. These data suggest that dynamic cilia localization of GPCRs depends on properties of individual receptors and cells where they are expressed. A better understanding of subcellular localization dynamics of ciliary GPCRs could reveal unknown molecular mechanisms regulating behaviors like feeding.Significance StatementOften, primary cilia localize specific G protein-coupled receptors (GPCRs) for subcellular signaling. Cell lines and model systems indicate that cilia deploy dynamic GPCR localization and change their shape or length to modulate signaling. We used mice to assess neuronal cilia GPCRs under physiological conditions associated with the receptors' known functions and ciliopathy clinical features like obesity. We show that particular cilia with specific GPCRs appear to dynamically alter their length while others appear relatively stable under these conditions. These results implicate multiple themes across cilia GPCR mediated signaling and indicate that not all cilia modulate GPCR signaling using the same mechanisms. These data will be important for potential pharmacological approaches to target cilia GPCR-mediated signaling.
    Keywords:  G protein-coupled receptors; accumbens; feeding behavior; hypothalamus; obesity; primary cilia
    DOI:  https://doi.org/10.1523/ENEURO.0360-22.2023
  8. Sci Signal. 2023 Feb 28. 16(774): eadd0645
    IHH, SHH, and primary cilia mediate epithelial-stromal cross-talk during decidualization in mice.
    Bo Li, Ya-Ping Yan, Yu-Ying He, Chen Liang, Meng-Yuan Li, Ying Wang, Zeng-Ming Yang.
      The establishment of pregnancy depends on interactions between the epithelial and stromal cells of the endometrium that drive the decidual reaction that remodels the stroma and enables embryo implantation. Decidualization in mice also depends on ovarian hormones and the presence of a blastocyst. Hedgehog signaling is transduced by primary cilia in many tissues and is involved in epithelial-stromal cross-talk during decidualization. We found that primary cilia on mouse uterine stromal cells increased in number and length during early pregnancy and were required for decidualization. In vitro and in vivo, progesterone promoted stromal ciliogenesis and the production of Indian hedgehog (IHH) in the epithelium and Sonic hedgehog (SHH) in the stroma. Blastocyst-derived TNF-α also induced epithelial IHH, which stimulated the production of SHH in the stroma through a mechanism that may involve the release of arachidonic acid from epithelial cells. In the stroma, SHH activated canonical Hedgehog signaling through primary cilia and promoted decidualization through a mechanism that depended on interleukin-11 (IL-11) and primary cilia. Our findings identify a primary cilia-dependent network that controls endometrial decidualization and suggest primary cilia as a candidate therapeutic target for endometrial diseases.
    DOI:  https://doi.org/10.1126/scisignal.add0645
  9. Clin Case Rep. 2023 Feb;11(2): e6692
    Compound heterozygosity of a de novo submicroscopic deletion and an inherited frameshift pathogenic variant in the PKHD1 gene in a fetus with bilaterally enlarged and echogenic kidneys, enlarged abdomen and oligohydramnios.
    Takuya Sakyu, Samantha R Stover, Yue Wang, Patricia Ward, Manisha Gandhi, Michael C Braun, Ignatia B Van den Veyver, Weimin Bi.
      We present a fetus with bilaterally enlarged and echogenic kidneys. Prenatal testing detected compound heterozygosity for a 0.676 Mb de novo deletion and an inherited pathogenic variant in PKHD1. This is the first case of autosomal recessive polycystic kidney disease (ARPKD) with a prenatally detected disease-causing PKHD1 deletion.
    Keywords:  22q11.21 microdeletion/duplication; ARPKD; PKHD1; autosomal recessive disorder; copy number variants; prenatal CMA
    DOI:  https://doi.org/10.1002/ccr3.6692
  10. Curr Biol. 2023 Feb 27. pii: S0960-9822(23)00021-0. [Epub ahead of print]33(4): R150-R153
    Cytoskeleton: The many flavors of cilia transition fibers.
    Jeroen Dobbelaere.
      Cilia are membrane-surrounded sensory cellular organelles that can also create motion to move fluids or propel the cell to which they are attached. New work shows that, whereas transition fibers are essential for cilia attachment to the membrane in most systems studied, transition fibers in Drosophila are only involved in cilia extension after docking.
    DOI:  https://doi.org/10.1016/j.cub.2023.01.021
  11. Toxics. 2023 Jan 30. pii: 134. [Epub ahead of print]11(2):
    Y-27632 Impairs Angiogenesis on Extra-Embryonic Vasculature in Post-Gastrulation Chick Embryos.
    Johannes W Duess, Jan-Hendrik Gosemann, Anna Kaskova Gheorghescu, Prem Puri, Jennifer Thompson.
      Y-27632 inhibits Rho-associated coiled-coil-containing protein kinase (ROCK) signaling, which is involved in various embryonic developmental processes, including angiogenesis, by controlling actin cytoskeleton assembly and cell contractility. Administration of Y-27632 impairs cytoskeletal arrangements in post-gastrulation chick embryos, leading to ventral body wall defects (VBWDs). Impaired angiogenesis has been hypothesized to contribute to VBWDs. ROCK is essential in transmitting signals downstream of vascular endothelial growth factor (VEGF). VEGF-mediated angiogenesis induces gene expressions and alterations of the actin cytoskeleton upon binding to VEGF receptors (VEGFRs). The aim of this study was to investigate effects of Y-27632 on angiogenesis in post-gastrulation chick embryos during early embryogenesis. After 60 h incubation, embryos in shell-less culture were treated with Y-27632 or vehicle for controls. Y-27632-treated embryos showed reduced extra-embryonic blood vessel formation with impaired circulation of the yolk sac, confirmed by fractal analysis. Western blot confirmed impaired ROCK downstream signaling by decreased expression of phosphorylated myosin light chain. Interestingly, RT-PCR demonstrated increased gene expression of VEGF and VEGFR-2 1 h post-treatment. Protein levels of VEGF were higher in Y-27632-treated embryos at 8 h following treatment, whereas no difference was seen in membranes. We hypothesize that administration of Y-27632 impairs vessel formation during angiogenesis, which may contribute to failure of VWB closure, causing VBWDs.
    Keywords:  ROCK; Y-27632; angiogenesis; chick embryo; post-gastrulation; ventral body wall defect
    DOI:  https://doi.org/10.3390/toxics11020134
  12. J Cell Physiol. 2023 Feb 28.
    RABL4/IFT27 in a nucleotide-independent manner promotes phospholipase D ciliary retrieval via facilitating BBSome reassembly at the ciliary tip.
    Yan-Xia Liu, Rui-Kai Zhang, Zhen-Chuan Fan.
      Certain ciliary transmembrane and membrane-associated signaling proteins export from cilia as intraflagellar transport (IFT) cargoes in a BBSome-dependent manner. Upon reaching the ciliary tip via anterograde IFT, the BBSome disassembles before being reassembled to form an intact entity for cargo phospholipase D (PLD) coupling. During this BBSome remodeling process, Chlamydomonas Rab-like 4 GTPase IFT27, by binding its partner IFT25 to form the heterodimeric IFT25/27, is indispensable for BBSome reassembly. Here, we show that IFT27 binds IFT25 in an IFT27 nucleotide-independent manner. IFT25/27 and the IFT subcomplexes IFT-A and -B are irrelevant for maintaining the stability of one another. GTP-loading onto IFT27 enhances the IFT25/27 affinity for binding to the IFT-B subcomplex core IFT-B1 entity in cytoplasm, while GDP-bound IFT27 does not prevent IFT25/27 from entering and cycling through cilia by integrating into IFT-B1. Upon at the ciliary tip, IFT25/27 cycles on and off IFT-B1 and this process is irrelevant with the nucleotide state of IFT27. During BBSome remodeling at the ciliary tip, IFT25/27 promotes BBSome reassembly independent of IFT27 nucleotide state, making postremodeled BBSomes available for PLD to interact with. Thus, IFT25/27 facilitates BBSome-dependent PLD export from cilia via controlling availability of intact BBSomes at the ciliary tip, while IFT27 nucleotide state does not participate in this regulatory event.
    Keywords:  BBSome; IFT25; IFT27; cilia; intraflagellar transport; phospholipase D
    DOI:  https://doi.org/10.1002/jcp.30945
  13. bioRxiv. 2023 Feb 23. pii: 2023.02.23.529616. [Epub ahead of print]
    MAP9/MAPH-9 supports axonemal microtubule doublets and modulates motor movement.
    Michael V Tran, James W Ferguson, Lauren E Cote, Daria Khuntsariya, Richard D Fetter, Jennifer T Wang, Stephen R Wellard, Maria D Sallee, Mariya Genova, Sani Eskinazi, Maria M Magiera, Carsten Janke, Tim Stearns, Zdenek Lansky, Kang Shen, Jérémy Magescas, Jessica L Feldman.
      Microtubule doublets (MTDs) are a well conserved compound microtubule structure found primarily in cilia. However, the mechanisms by which MTDs form and are maintained in vivo remain poorly understood. Here, we characterize microtubule-associated protein 9 (MAP9) as a novel MTD-associated protein. We demonstrate that C. elegans MAPH-9, a MAP9 homolog, is present during MTD assembly and localizes exclusively to MTDs, a preference that is in part mediated by tubulin polyglutamylation. Loss of MAPH-9 caused ultrastructural MTD defects, dysregulated axonemal motor velocity, and perturbed cilia function. As we found that the mammalian ortholog MAP9 localized to axonemes in cultured mammalian cells and mouse tissues, we propose that MAP9/MAPH-9 plays a conserved role in supporting the structure of axonemal MTDs and regulating ciliary motors.
    DOI:  https://doi.org/10.1101/2023.02.23.529616
  14. Sultan Qaboos Univ Med J. 2023 Feb;23(1): 76-80
    Cilia Ultrastructure Associated with Primary Ciliary Dyskinesia in Omani Patients.
    Kawther Al Adawi, Taher Baomar, Marwa Al Riyami, Nawal Al Shamli, Khoula Al Shidhani, Aliya Al Ansari, Hussein Al Kindi.
      Objectives: Primary ciliary dyskinesia (PCD) is a disorder affecting the structure and function of the motile cilia of the respiratory system. Transmission electron microscopy is one method that can be used to examine ciliary ultrastructure in airway biopsies. Although the role of ultrastructural findings in PCD has been described in the literature, this role has not been well-studied in the Middle East or, specifically, Oman. This study aimed to describe ultrastructural features in Omani patients with high suspicion of PCD.Methods: This retrospective cross-sectional study included 129 adequate airway biopsies obtained from Omani patients attending pulmonary clinics at Sultan Qaboos University Hospital and the Royal Hospital, Muscat, Oman, from 2010 to 2020 who were suspected of having PCD.
    Results: Ciliary ultrastructural abnormalities in the current study population were outer dynein arm (ODA) associated with inner dynein arm (IDA) defects (8%), microtubular disorganisation associated with IDA defect (5%) and isolated ODA defect (2%). Most of the biopsies showed normal ultrastructure (82%).
    Conclusion: In Omani patients suspected to have PCD, normal ultrastructure was the most common feature.
    Keywords:  Biopsy; Cilia; Oman; Primary Ciliary Dyskinesia; Transmission Electron Microscopy; Ultrastructure
    DOI:  https://doi.org/10.18295/squmj.4.2022.029
  15. J Assist Reprod Genet. 2023 Mar 01.
    Characterization of a DRC1 null variant associated with primary ciliary dyskinesia and female infertility.
    R Pereira, V Carvalho, C Dias, T Barbosa, J Oliveira, Â Alves, E Oliveira, R Sá, M Sousa.
      PROPOSE: We here present a female case with primary ciliary dyskinesia (PCD) and infertility. In this report, we also present the evaluation of the patient family, including her twin sister, also with PCD and infertility.METHODS: Confirmation of the PCD clinical diagnosis was performed through assessment of cilia motility, by high-speed video microscopy (HSVM), axoneme ultrastructure, by transmission electron microscopy (TEM), and genetic characterization, by whole-exome sequence (WES). Gene expression studies used qPCR for mRNA expression and immunofluorescence to determine cell protein localization.
    RESULTS: We identified a homozygous nonsense variant in the DRC1 gene (NM 145038.5:c.352C>T (p.Gln118Ter)) in the female patient with PCD and infertility that fit the model of autosomal recessive genetic transmission. This variant eventually results in a dyskinetic ciliary beat with a lower frequency and a partial lack of both dynein arms as revealed by TEM analysis. Moreover, this variant implies a decrease in the expression of DRC1 mRNA and protein. Additionally, expression analysis suggested that DRC1 may interact with other DRC elements.
    CONCLUSIONS: Our findings suggest that the DRC1 null variant leads to PCD associated with infertility, likely caused by defects in axoneme from Fallopian tube cilia. Overall, our outcomes contribute to a better understanding of the genetic factors involved in the pathophysiology of PCD and infertility, and they highlight the interaction of different genes in the patient phenotype, which should be investigated further because it may explain the high heterogeneity observed in PCD patients.
    Keywords:  Cystic bronchiectasis; DRC1; Female infertility; Primary ciliary dyskinesia; Recurrent otitis media; Twin sister
    DOI:  https://doi.org/10.1007/s10815-023-02755-6
  16. J Clin Invest. 2023 Mar 02. pii: e161156. [Epub ahead of print]
    CEP162 deficiency causes human retinal degeneration and reveals a dual role in ciliogenesis and neurogenesis.
    Nafisa Nuzhat, Kristof Van Schil, Sandra Liakopoulos, Miriam Bauwens, Alfredo Dueñas Rey, Stephan Käseberg, Melanie Jäger, Jason R Willer, Jennifer Winter, Hanh M Truong, Nuria Gruartmoner, Mattias Van Heetvelde, Joachim C Wolf, Robert Merget, Sabine Grasshoff-Derr, Jo Van Dorpe, Anne Hoorens, Heidi Stöhr, Luke Mansard, Anne-Françoise Roux, Thomas Langmann, Katharina Dannhausen, David Rosenkranz, Karl M Wissing, Michel Van Lint, Heidi Rossmann, Friederike Häuser, Peter Nürnberg, Holger Thiele, Ulrich Zechner, Jillian N Pearring, Elfride De Baere, Hanno J Bolz.
      Defects in primary or motile cilia result in a variety of human pathologies, and retinal degeneration is frequently associated with these so-called ciliopathies. We found that homozygosity for a truncating variant in CEP162, a centrosome and microtubule-associated protein required for transition zone assembly during ciliogenesis and neuronal differentiation in the retina, caused late-onset retinitis pigmentosa in 2 unrelated families. The mutant CEP162-E646R*5 protein was expressed and properly localized to the mitotic spindle, but was missing from the basal body in primary and photoreceptor cilia. This impaired recruitment of transition zone components to the basal body and corresponded to complete loss of CEP162 function at the ciliary compartment, reflected by delayed formation of dysmorphic cilia. In contrast, shRNA knockdown of Cep162 in the developing mouse retina increased cell death, which was rescued by expression of CEP162-E646R*5, indicating that the mutant retains its role for retinal neurogenesis. Human retinal degeneration thus resulted from specific loss of the ciliary function of CEP162.
    Keywords:  Cell Biology; Genetic diseases; Genetics; Molecular genetics; Retinopathy
    DOI:  https://doi.org/10.1172/JCI161156
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