bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2022‒07‒10
thirteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)
  1. [Tolvaptan, a vasopressin V2 receptor antagonist, is the world's first approved drug for treatment of autosomal dominant polycystic kidney disease (ADPKD)].
  2. Identification of osteopontin as a urinary biomarker for autosomal dominant polycystic kidney disease progression.
  3. Development of an enterocutaneous fistula from an intestinal perforation in a patient with autosomal dominant polycystic kidney disease.
  4. Mini kidney organoids deliver maximal drug screening impact.
  5. Primary cilia control translation and the cell cycle in medulloblastoma.
  6. GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review.
  7. A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery.
  8. A novel approach to establishing a temporomandibular joint fibrocartilage cell line.
  9. Molecular targets of primary cilia defects in cancer (Review).
  10. Combined Preimplantation Genetic Testing for Genetic Kidney Disease: Genetic Risk Identification, Assisted Reproductive Cycle, and Pregnancy Outcome Analysis.
  11. Efficacy of Prolonged Antibiotic Therapy for Renal Cyst Infections in Polycystic Kidney Disease.
  12. The divergent roles of exosomes in kidney diseases: Pathogenesis, diagnostics, prognostics and therapeutics.
  13. Ciliary Proteins Repurposed by the Synaptic Ribbon: Trafficking Myristoylated Proteins at Rod Photoreceptor Synapses.
  1. Nihon Yakurigaku Zasshi. 2022 ;157(4): 254-260
    [Tolvaptan, a vasopressin V2 receptor antagonist, is the world's first approved drug for treatment of autosomal dominant polycystic kidney disease (ADPKD)].
    Yoshihisa Yamada, Hiroyuki Fujiki, Hiroshi Mizuguchi, Yukinobu Takeshita, Katsuji Hattori, Koji Ohmoto, Miki Aihara, Keisuke Nagano, Yoshimasa Isakari, Miho Yamamoto, Yoshitaka Yamamura.
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. Fluid-filled cysts develop and enlarge in both kidneys, eventually leading to kidney failure. Tolvaptan is a selective vasopressin V2 receptor antagonist and the first and only drug approved for treatment of ADPKD. It blocks binding of arginine vasopressin (AVP) to V2 receptors in the collecting duct of kidney, thereby inducing water diuresis (aquaresis) without losing electrolytes. Therefore, tolvaptan was originally developed and approved as the first oral aquaretic agent for treatment of hyponatremia and fluid volume overload in heart failure and cirrhosis. During the development of tolvaptan as aquaretics, efficacy of V2 antagonist in polycystic kidney animal model was reported and then the development of tolvaptan for ADPKD was also initiated. Cyclic adenosine monophosphate (cAMP) plays an important role in cyst growth by promoting cell proliferation and fluid secretion. Tolvaptan showed suppression of cyst growth through inhibiting AVP-induced cAMP production and delayed the onset of end-stage renal disease in an animal model. In the phase 3 clinical trial in ADPKD patients (TEMPO 3:4 trial), 3-year treatment with tolvaptan slowed the disease progression including increase of kidney volume and decline in renal function. Efficacy of tolvaptan in patients with late-stage ADPKD was confirmed in another 1-year phase 3 REPRISE trial. Tolvaptan is approved for treatment of ADPKD in more than 40 countries and we expect it can contribute to more ADPKD patients worldwide. We also expect that drugs with new mechanisms will be available in the near future.
    DOI:  https://doi.org/10.1254/fpj.22006
  2. Kidney Res Clin Pract. 2022 Jun 20.
    Identification of osteopontin as a urinary biomarker for autosomal dominant polycystic kidney disease progression.
    Hyunsuk Kim, Jinmo Sung, Ju Young Bae, Poongyeon Lee, Yun Kyu Oh, Hyunho Kim.
      Background: Autosomal dominant polycystic kidney disease (ADPKD), one of the most common human monogenic diseases, is characterized by the presence of numerous fluid-filled renal cysts and is a leading cause of end-stage renal disease (ESRD). Urinary biomarkers may be useful for predicting the variable course of ADPKD progression from cyst growth to ESRD.Methods: To identify candidate urinary biomarkers of ADPKD progression, we used CRISPR/Cas9 genome editing to generate porcine fibroblasts with mono- and biallelic ADPKD gene knockout (PKD2+/- and PKD2-/-, respectively). We then performed RNA-sequencing analysis on these cells.
    Results: Levels of osteopontin (OPN), which is expressed by renal epithelial tubular cells and excreted into urine, were reduced in PKD2-/- cells but not in PKD2+/- cells. OPN levels were also reduced in the renal cyst cells of ADPKD patients. Next, we investigated whether OPN excretion was decreased in patients with ADPKD via enzyme-linked immunosorbent assay. OPN levels excreted into renal cyst cell culture media and urine from ADPKD patients were decreased. To investigate whether OPN can predict the rate of ADPKD progression, we compared urinary excretion of OPN in ADPKD patients with slow progression and those with rapid progression. Those with rapid progression had an estimated glomerular filtration rate of >60 mL/min/1.73 m2. Urinary OPN excretion levels were lower in rapid progressors than in slow progressors.
    Conclusion: These findings suggest that OPN is a useful urinary biomarker for predicting ADPKD progression.
    Keywords:  Autosomal dominant polycystic kidney; Biomarkers; CRISPR/Cas9; Osteopontin
    DOI:  https://doi.org/10.23876/j.krcp.21.303
  3. CEN Case Rep. 2022 Jul 05.
    Development of an enterocutaneous fistula from an intestinal perforation in a patient with autosomal dominant polycystic kidney disease.
    Yuki Nakayama, Naoki Sawa, Tatsuya Suwabe, Akinari Sekine, Masayuki Yamanouchi, Daisuke Ikuma, Hiroki Mizuno, Yuki Oba, Eiko Hasegawa, Junichi Hoshino, Shuichiro Matoba, Yoshifumi Ubara.
      We herein report a case of enterocutaneous fistula in a patient with autosomal dominant polycystic kidney disease (ADPKD). A 37-year-old Japanese man was admitted to our hospital. Three months prior to transfer to our hospital, he developed intense flank pain with gross hematuria. His serum creatinine had decreased to 7.8 mg/dL and hemodialysis was started, but gross hematuria persisted and he developed hypotension. Upon admission, plain chest radiography did not reveal any free air, but computed tomography (CT) showed generalized ventral subcutaneous air from the head to the lower extremities and enlarged kidneys. Enterography showed leakage of contrast medium from the descending colon into the subcutaneous area. C-reactive protein was 23.1 mg/dL. A colostomy was placed in the transverse colon proximal to the perforation, and systemic subcutaneous drainage was performed. The fever subsequently resolved, and the C-reactive protein test became negative. Three months later, renal artery embolization was performed, and 12 months thereafter, CT showed a marked decrease in kidney size. We assume that a markedly enlarged kidney leaded to intestinal perforation, which developed into an enterocutaneous fistula. Consequently, intestinal fluid leaked into the subcutaneous cavity of the abdominal wall and spread systemically, resulting in extensive subcutaneous abscesses.
    Keywords:  Autosomal dominant polycystic kidney disease (ADPKD); Enterocutaneous fistula; Intestinal perforation; Transcatheter arterial embolization (TAE)
    DOI:  https://doi.org/10.1007/s13730-022-00716-z
  4. Cell Stem Cell. 2022 Jul 07. pii: S1934-5909(22)00258-2. [Epub ahead of print]29(7): 1011-1012
    Mini kidney organoids deliver maximal drug screening impact.
    Eryn E Dixon, Shayna T J Bradford, Benjamin D Humphreys.
      In this issue of Cell Stem Cell, Tran and colleagues develop a platform for differentiating thousands of miniature kidney organoids consisting of one or two nephron-like structures each. They use this platform to identify a potent new inhibitor of cyst growth in organoid models of autosomal-dominant polycystic kidney disease.
    DOI:  https://doi.org/10.1016/j.stem.2022.06.009
  5. Genes Dev. 2022 Jul 07.
    Primary cilia control translation and the cell cycle in medulloblastoma.
    Yong Ha Youn, Shirui Hou, Chang-Chih Wu, Daisuke Kawauchi, Brent A Orr, Giles W Robinson, David Finkelstein, Makoto M Taketo, Richard J Gilbertson, Martine F Roussel, Young-Goo Han.
      The primary cilium, a signaling organelle projecting from the surface of a cell, controls cellular physiology and behavior. The presence or absence of primary cilia is a distinctive feature of a given tumor type; however, whether and how the primary cilium contributes to tumorigenesis are unknown for most tumors. Medulloblastoma (MB) is a common pediatric brain cancer comprising four groups: SHH, WNT, group 3 (G3), and group 4 (G4). From 111 cases of MB, we show that primary cilia are abundant in SHH and WNT MBs but rare in G3 and G4 MBs. Using WNT and G3 MB mouse models, we show that primary cilia promote WNT MB by facilitating translation of mRNA encoding β-catenin, a major oncoprotein driving WNT MB, whereas cilium loss promotes G3 MB by disrupting cell cycle control and destabilizing the genome. Our findings reveal tumor type-specific ciliary functions and underlying molecular mechanisms. Moreover, we expand the function of primary cilia to translation control and reveal a molecular mechanism by which cilia regulate cell cycle progression, thereby providing new frameworks for studying cilium function in normal and pathologic conditions.
    Keywords:  WNT; cell cycle; cilia; medulloblastoma; translation
    DOI:  https://doi.org/10.1101/gad.349596.122
  6. Int J Mol Sci. 2022 Jul 01. pii: 7373. [Epub ahead of print]23(13):
    GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review.
    Roberto De Masi, Stefania Orlando.
      Glycans are one of the four fundamental macromolecular components of living matter, and they are highly regulated in the cell. Their functions are metabolic, structural and modulatory. In particular, ER resident N-glycans participate with the Glc3Man9GlcNAc2 highly conserved sequence, in protein folding process, where the physiological balance between glycosylation/deglycosylation on the innermost glucose residue takes place, according GANAB/UGGT concentration ratio. However, under abnormal conditions, the cell adapts to the glucose availability by adopting an aerobic or anaerobic regimen of glycolysis, or to external stimuli through internal or external recognition patterns, so it responds to pathogenic noxa with unfolded protein response (UPR). UPR can affect Multiple Sclerosis (MS) and several neurological and metabolic diseases via the BiP stress sensor, resulting in ATF6, PERK and IRE1 activation. Furthermore, the abnormal GANAB expression has been observed in MS, systemic lupus erythematous, male germinal epithelium and predisposed highly replicating cells of the kidney tubules and bile ducts. The latter is the case of Polycystic Liver Disease (PCLD) and Polycystic Kidney Disease (PCKD), where genetically induced GANAB loss affects polycystin-1 (PC1) and polycystin-2 (PC2), resulting in altered protein quality control and cyst formation phenomenon. Our topics resume the role of glycans in cell physiology, highlighting the N-glycans one, as a substrate of GANAB, which is an emerging key molecule in MS and other human pathologies.
    Keywords:  ER stress; GANAB; Multiple Sclerosis; PRKCSH; Polycystic Kidney Disease; Polycystic Liver Disease
    DOI:  https://doi.org/10.3390/ijms23137373
  7. Cell Stem Cell. 2022 Jul 07. pii: S1934-5909(22)00254-5. [Epub ahead of print]29(7): 1083-1101.e7
    A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery.
    Tracy Tran, Cheng Jack Song, Trang Nguyen, Shun-Yang Cheng, Jill A McMahon, Rui Yang, Qiuyu Guo, Balint Der, Nils O Lindström, Daniel C-H Lin, Andrew P McMahon.
      Human pluripotent stem-cell-derived organoids are models for human development and disease. We report a modified human kidney organoid system that generates thousands of similar organoids, each consisting of 1-2 nephron-like structures. Single-cell transcriptomic profiling and immunofluorescence validation highlighted patterned nephron-like structures utilizing similar pathways, with distinct morphogenesis, to human nephrogenesis. To examine this platform for therapeutic screening, the polycystic kidney disease genes PKD1 and PKD2 were inactivated by gene editing. PKD1 and PKD2 mutant models exhibited efficient and reproducible cyst formation. Cystic outgrowths could be propagated for months to centimeter-sized cysts. To shed new light on cystogenesis, 247 protein kinase inhibitors (PKIs) were screened in a live imaging assay identifying compounds blocking cyst formation but not overall organoid growth. Scaling and further development of the organoid platform will enable a broader capability for kidney disease modeling and high-throughput drug screens.
    Keywords:  developmental trajectory; disease modeling; drug screen; high throughput; kidney development; kidney organoid; nephron development; phenotypic screen; polycystic kidney disease; scRNA-seq
    DOI:  https://doi.org/10.1016/j.stem.2022.06.005
  8. J Dent Sci. 2022 Jul;17(3): 1378-1386
    A novel approach to establishing a temporomandibular joint fibrocartilage cell line.
    Yusen Qiao, Dan Yi, David Andrew Reed, Louis G Mercuri, Di Chen, Chun-do Oh.
      Background/purpose: The temporomandibular joint (TMJ) is a bi-arthrodial joint that is composed of the temporal bone glenoid fossa and the condylar head of the mandible both having fibrocartilaginous articular surfaces. Functional overloading of the TMJ is the main cause of TMJ osteoarthritis (TMJ OA) disease. The aim of this study was to establish immortalized TMJ fibrocartilage cell clones to provide enough cells to adequately investigate the molecular mechanisms studies of TMJ OA.Materials and methods: We have isolated temporomandibular condyle chondrocytes from adult Sprague Dawley rat. The cells were cultured and immortalized by treating with Y-27632, a well-characterized inhibitor of Rho-Associated Kinase (ROCK). Clones were characterized on the basis of cell morphology and analyses of marker gene expression through 45 passages.
    Results: Cells from the condylar fibrocartilage of the TMJ were successfully immortalized by ROCK inhibitor, retaining a consistent cuboidal cell morphology and the expression of several cell markers of polymorphic cell fate. In addition, they retained phenotype features similar to the primary parental TMJ fibrocartilage cells when the cells were challenged with different cytokines and growth factors.
    Conclusion: These studies establish a novel immortalized cell line through ROCK inhibitor Y-27632, that retains the polymorphic phenotype of primary cell lines from TMJ fibrocartilage chondrocyte cell through a high number of passages, serving as a valuable preclinical resource for mechanistic in vitro assessment of TMJ health, disease, and regeneration.
    Keywords:  Immortalization; Rho-associated kinase inhibitor; TMJ fibrocartilage cell
    DOI:  https://doi.org/10.1016/j.jds.2022.04.017
  9. Int J Oncol. 2022 Aug;pii: 98. [Epub ahead of print]61(2):
    Molecular targets of primary cilia defects in cancer (Review).
    Fengying Yin, Zihao Wei, Fangman Chen, Chuan Xin, Qianming Chen.
      Primary cilia are hair‑like organelles that are present on the majority of mammalian cells. They are regarded as the regulatory 'hub' of cell functions due to their indispensable roles for several signaling pathways, such as Hh and Wnt pathways. Originally, cilia defects were found to cause a panoply of human diseases commonly referred to as 'ciliopathies'. Evidence is accumulating that cilia defects are involved in the onset and development of cancer. Some proteins that cause cilia defects have been identified as oncogenes in multiple cancer types. Hence, understanding the pathways that cause cilia defects in cancer is of utmost importance for the development of novel cancer therapeutic targets. The present review article provides a critical overview of the molecular targets of primary cilia defects in cancer, and highlights their vast potential as therapeutic targets and novel biomarkers.
    Keywords:  biomarker; cancer; molecular target; primary cilia
    DOI:  https://doi.org/10.3892/ijo.2022.5388
  10. Front Med (Lausanne). 2022 ;9 936578
    Combined Preimplantation Genetic Testing for Genetic Kidney Disease: Genetic Risk Identification, Assisted Reproductive Cycle, and Pregnancy Outcome Analysis.
    Min Xiao, Hua Shi, Jia Rao, Yanping Xi, Shuo Zhang, Junping Wu, Saijuan Zhu, Jing Zhou, Hong Xu, Caixia Lei, Xiaoxi Sun.
      Background: Genetic kidney disease is a major cause of morbidity and mortality in neonates and end-stage renal disease (ESRD) in children and adolescents. Genetic diagnosis provides key information for early identification of congenital kidney disease and reproductive risk counseling. Preimplantation genetic testing for monogenic disease (PGT-M) as a reproductive technology helps prospective parents to prevent passing on disease-causing mutations to their offspring.Materials and Methods: A retrospective cohort of couples counseled on PGT who had a risk to given birth to a child with genetic kidney disease or had a history of prenatal fetal kidney and urinary system development abnormalities from 2011 to 2021. Through a combination of simultaneously screening for aneuploidy and monogenic kidney disease, we achieved reproductive genetic intervention.
    Results: A total of 64 couples counseled on PGT for monogenic kidney disease in a single reproductive center during the past 10 years, of whom 38 different genetic kidney diseases were identified. The most frequent indications for referral were autosomal recessive disease (54.7%), then autosomal dominant disease (29.7%), and X-linked disease (15.6%). Polycystic kidney disease was the most common diseases counted for 34.4%. After oocyte-retrieval in all of 64 females, a total of 339 embryos were diagnosed and 63 embryos were transferred in succession. Among 61 cycles of frozen-embryo transfer (FET), ongoing pregnancy/live birth rate (OP/LBR) reached 57.38%. The cumulative OP/LBR in our cohort for the 64 couples was 54.69%. In addition, we have carried out expanded carrier screening (ECS) in all the in vitro fertilization (IVF) couples performed PGT covering 7,311 individuals. The carrier frequency of the candidate genes for monogenic kidney diseases accounted for 12.19%.
    Conclusion: Overall, the customization PGT-M plan in our IVF center is pivotal to decreasing the morbidity and implementing reproductive genetic intervention of genetic kidney disease.
    Keywords:  expanded carrier screening; haplotype analysis; monogenic kidney disease; pregnancy outcomes; preimplantation genetic testing
    DOI:  https://doi.org/10.3389/fmed.2022.936578
  11. Mayo Clin Proc. 2022 Jul;pii: S0025-6196(22)00061-1. [Epub ahead of print]97(7): 1305-1317
    Efficacy of Prolonged Antibiotic Therapy for Renal Cyst Infections in Polycystic Kidney Disease.
    Julien Dang, Anne Scemla, Charlotte Loheac, Anis Chaba, Frank Bienaimé, Dominique Joly, Christophe Legendre, Bertrand Knebelmann, Caroline Charlier.
      OBJECTIVE: To determine the impact of antibiotic therapy (ATBT) on outcomes of renal cyst infection (CyI) in patients with polycystic kidney disease.PATIENTS AND METHODS: We undertook a single-center retrospective study of CyI in autosomal dominant polycystic kidney disease (January 1, 2000, through December 31, 2018). Cyst infections were classified as definite (microbiologically proven), probable (radiologic signs), or possible (clinical or biologic signs only). We studied the determinants of ATBT failure (persistence of infection beyond 72 hours of microbiologically adequate initial ATBT, with requirement for ATBT change, cyst drainage, or nephrectomy) and recurrences (>14 days after the end of ATBT).
    RESULTS: Among 90 patients, 139 CyIs (11 definite, 74 probable, 54 possible) were compiled. Cultures were positive in 106 of 139 (76%) episodes, with Escherichia coli found in 89 of 106 (84%). Treatment failures and recurrences within 1 year of follow-up were more frequent in definite/probable CyI (20/85 [34%] and 16/85 [19%]) than in possible CyI (2/54 [4%] and 4/54 [7%]; P<.01 and P=.08, respectively). Male sex (odds ratio [OR], 7.79; 95% CI, 1.72 to 46.68; P<.01), peak C-reactive protein level above 250 mg/L (OR, 7.29; 95% CI, 1.78 to 35.74; P<.01; to convert C-reactive protein values to nmol/L, multiply by 9.524), and cyst wall thickening (OR, 7.70; 95% CI, 1.77 to 43.47; P=.01) but not the modalities of initial ATBT were independently associated with higher risk of failure. In a Cox proportional hazards model, kidney transplant recipients exhibited higher risk of recurrence (hazard ratio, 3.76; 95% CI, 1.06 to 13.37; P=.04), whereas a total duration of ATBT of 28 days or longer was protective (hazard ratio, 0.02; 95% CI, 0.00 to 0.16; P<.001), with an inverse correlation between duration and recurrence (81% for treatment <21 days, 47% for 21 to 27 days, 2% for ≥28 days; P<.0001).
    CONCLUSION: Initial first-line ATBT had no significant effect on renal CyI treatment failure. Treatment duration of 28 days and longer reduced recurrences.
    DOI:  https://doi.org/10.1016/j.mayocp.2022.01.027
  12. Int J Biochem Cell Biol. 2022 Jul 01. pii: S1357-2725(22)00107-8. [Epub ahead of print] 106262
    The divergent roles of exosomes in kidney diseases: Pathogenesis, diagnostics, prognostics and therapeutics.
    Visith Thongboonkerd, Rattiyaporn Kanlaya.
      Exosomes are the self-packed nanoscale vesicles (nanovesicles) derived from late endosomes and released from the cells to the extracellular milieu. Exosomal biogenesis is based on endosomal pathway to form the nanovesicles surrounded by membrane originated from plasma membranes of the parental cells. During biogenesis, exosomes selectively encapsulate an array of biomolecules (proteins, nucleic acids, lipids, metabolites, etc.), thereby conveying diverse messages for cell-cell communications. Once released, these exosomal contents trigger signaling and trafficking that play roles in cell growth, development, immune responses, homeostasis, remodeling, etc. Recent advances in exosomal research have provided a wealth of useful information that enhances our knowledge on the roles for exosomes in pathogenic mechanisms of human diseases involving a wide variety of organ systems. In the kidney, exosomes play divergent roles, ranging from pathogenesis to therapeutics, based on their original sources and type of interventions. Herein, we summarize and update the current knowledge on the divergent roles of exosomes involving the pathogenesis, diagnostics, prognostics, and therapeutics in various groups of kidney diseases, including acute kidney injury, immune-mediated kidney diseases (e.g., IgA nephropathy, lupus nephritis, membranous nephropathy, focal segmental glomerulosclerosis), chronic kidney disease (caused by diabetic nephropathy and others), renal cell carcinoma, nephrolithiasis, kidney transplantation and related complications, and polycystic kidney disease. Finally, the future perspectives on research in this area are discussed.
    Keywords:  AKI; Biomarkers; CKD; Diabetic nephropathy; IgA nephropathy; Kidney stone; Lupus; Polycystic kidney; Renal cell carcinoma; Transplantation
    DOI:  https://doi.org/10.1016/j.biocel.2022.106262
  13. Int J Mol Sci. 2022 Jun 27. pii: 7135. [Epub ahead of print]23(13):
    Ciliary Proteins Repurposed by the Synaptic Ribbon: Trafficking Myristoylated Proteins at Rod Photoreceptor Synapses.
    Shweta Suiwal, Mayur Dembla, Karin Schwarz, Rashmi Katiyar, Martin Jung, Yvonne Carius, Stephan Maxeiner, Marcel A Lauterbach, C Roy D Lancaster, Frank Schmitz.
      The Unc119 protein mediates transport of myristoylated proteins to the photoreceptor outer segment, a specialized primary cilium. This transport activity is regulated by the GTPase Arl3 as well as by Arl13b and Rp2 that control Arl3 activation/inactivation. Interestingly, Unc119 is also enriched in photoreceptor synapses and can bind to RIBEYE, the main component of synaptic ribbons. In the present study, we analyzed whether the known regulatory proteins, that control the Unc119-dependent myristoylated protein transport at the primary cilium, are also present at the photoreceptor synaptic ribbon complex by using high-resolution immunofluorescence and immunogold electron microscopy. We found Arl3 and Arl13b to be enriched at the synaptic ribbon whereas Rp2 was predominantly found on vesicles distributed within the entire terminal. These findings indicate that the synaptic ribbon could be involved in the discharge of Unc119-bound lipid-modified proteins. In agreement with this hypothesis, we found Nphp3 (Nephrocystin-3), a myristoylated, Unc119-dependent cargo protein enriched at the basal portion of the ribbon in close vicinity to the active zone. Mutations in Nphp3 are known to be associated with Senior-Løken Syndrome 3 (SLS3). Visual impairment and blindness in SLS3 might thus not only result from ciliary dysfunctions but also from malfunctions of the photoreceptor synapse.
    Keywords:  Arl13b; Arl3; Nphp3; immunogold electron microscopy; photoreceptor synapse; retina; synaptic ribbon
    DOI:  https://doi.org/10.3390/ijms23137135
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