bims-bicyki 2023-08-13 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2023–08–13
thirteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Scar Epilepsy as a Complication of Subarachnoid Hemorrhage in a Patient With Adult Polycystic Kidney Disease: A Case Report.
Abdominal Imaging in ADPKD: Beyond Total Kidney Volume.
Targeted Next Generation Sequencing Revealed Novel Variants in the PKD1 and PKD2 Genes of Iranian Patients with Autosomal Dominant Polycystic Kidney Disease.
TTLL12 is required for primary ciliary axoneme formation in polarized epithelial cells.
[The regulatory role and mechanism of primary cilia in craniofacial and dental development].
Polycystic kidneys: interaction of notch and renin.
Tau tubulin kinase 1 and 2 regulate ciliogenesis and human pluripotent stem cells-derived neural rosettes.
Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused by IFT74 mutations.
Diet and Polycystic Kidney Disease: Nutrients, Foods, Dietary Patterns, and Implications for Practice.
Novel centriolar defects underlie a primary ciliary dyskinesia phenotype in an adenylate kinase 7 deficient ciliated epithelium.
Interaction Between Determinants Governing Urine Volume in Patients With ADPKD on Tolvaptan and its Impact on Quality of Life.
Primary cilia: Structure, dynamics, and roles in cancer cells and tumor microenvironment.
Broadening horizons: the multifaceted functions of ferroptosis in kidney diseases.

Cureus. 2023 Jul;15(7): e41537

Scar Epilepsy as a Complication of Subarachnoid Hemorrhage in a Patient With Adult Polycystic Kidney Disease: A Case Report.

Adil Khan, Maryem Anwar, Farah N Zaidi, Shaima Ghabsha, Anees Ur Rehman.

  Polycystic kidney disease (PKD) is the most common hereditary disorder of kidneys. In adults, PKD1 gene mutation almost always signifies its subtype, autosomal dominant polycystic kidney disease (ADPKD), or adult polycystic kidney disease. ADPKD is a multisystemic disorder giving rise to renal and extra-renal manifestations. The renal shutdown is the most feared renal complication while the development of intracranial aneurysms is considered the most lethal extra-renal feature. This can be attributed to the increased risk of rupture associated with aneurysms leading to a condition called subarachnoid hemorrhage (SAH). While being notorious for the subtle situations SAH often leads to, its association with the onset of seizures is a matter of high clinical significance. We present a patient with a kidney disorder (ADPKD) that has led to the onset of epilepsy. Five years after the diagnosis of ADPKD, he developed an aneurysm in the right internal carotid artery, for which he was treated conservatively. After four months, he presented with the onset of symptoms of SAH, which was confirmed by computed tomography angiography. Clipping was unable to be performed, and the patient was treated conservatively, this time as well. Recently, the patient presented with the onset of generalized tonic-clonic seizures, unable to be controlled with single anti-epileptics. He was stabilized by dual intravenous antiepileptics but on further workup, he was found to have a recurrence of a berry aneurysm for which he was referred to a neurosurgeon for a clipping procedure to be performed. The operation was successful, but the patient was still found to be an epileptic for which he was discharged with a long-term course of double anti-epileptics.

Keywords:  aneurysmal subarachnoid hemorrhage; berry aneurysm; computed tomography angiogram; generalized tonic-clonic seizures; polycystic kidney disease (pkd)

DOI:  https://doi.org/10.7759/cureus.41537
J Clin Med. 2023 Aug 05. pii: 5133. [Epub ahead of print]12(15):

Abdominal Imaging in ADPKD: Beyond Total Kidney Volume.

Anna Caroli, Timothy L Kline.

  In the context of autosomal dominant polycystic kidney disease (ADPKD), measurement of the total kidney volume (TKV) is crucial. It acts as a marker for tracking disease progression, and evaluating the effectiveness of treatment strategies. The TKV has also been recognized as an enrichment biomarker and a possible surrogate endpoint in clinical trials. Several imaging modalities and methods are available to calculate the TKV, and the choice depends on the purpose of use. Technological advancements have made it possible to accurately assess the cyst burden, which can be crucial to assessing the disease state and helping to identify rapid progressors. Moreover, the development of automated algorithms has increased the efficiency of total kidney and cyst volume measurements. Beyond these measurements, the quantification and characterization of non-cystic kidney tissue shows potential for stratifying ADPKD patients early on, monitoring disease progression, and possibly predicting renal function loss. A broad spectrum of radiological imaging techniques are available to characterize the kidney tissue, showing promise when it comes to non-invasively picking up the early signs of ADPKD progression. Radiomics have been used to extract textural features from ADPKD images, providing valuable information about the heterogeneity of the cystic and non-cystic components. This review provides an overview of ADPKD imaging biomarkers, focusing on the quantification methods, potential, and necessary steps toward a successful translation to clinical practice.

Keywords:  artificial intelligence; autosomal dominant polycystic kidney disease; cyst volume; magnetic resonance imaging; non-cystic tissue; segmentation; total kidney volume

DOI:  https://doi.org/10.3390/jcm12155133
Arch Iran Med. 2022 09 01. 25(9): 600-608

Targeted Next Generation Sequencing Revealed Novel Variants in the PKD1 and PKD2 Genes of Iranian Patients with Autosomal Dominant Polycystic Kidney Disease.

Maryam Hosseinpour, Fariba Ardalani, Marzieh Mohseni, Maryam Beheshtian, Sanaz Arzhangi, Shahrzad Ossareh, Hossein Najmabadi, Ali Nobakht, Kimia Kahrizi, Behrooz Broumand.

   BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), one of the common inherited disorders in humans, is characterized by the development and enlargement of renal cysts, often leading to end-stage renal disease (ESRD). In this study, Iranian ADPKD families were subjected to high-throughput DNA sequencing to find potential causative variants facilitating the way toward risk assessment and targeted therapy.
METHODS: Our protocol was based on the targeted next generation sequencing (NGS) panel previously developed in our center comprising 12 genes involved in PKD. This panel has been applied to investigate the genetic causes of 32 patients with a clinical suspicion of ADPKD.
RESULTS: We identified a total of 31 variants for 32 individuals, two of which were each detected in two individuals. Twenty-seven out of 31 detected variants were interpreted as pathogenic/likely pathogenic and the remaining 4 of uncertain significance with a molecular diagnostic success rate of 87.5%. Among these variants, 25 PKD1/2 pathogenic/likely pathogenic variants were detected in 32 index patients (78.1%), and variants of uncertain significance in four individuals (12.5% in PKD1/2). The majority of variants was identified in PKD1 (74.2%). Autosomal recessive PKD was identified in one patient, indicating the similarities between recessive and dominant PKD. In concordance with earlier studies, this biallelic PKD1 variant, p.Arg3277Cys, leads to rapidly progressive and severe disease with very early-onset ADPKD.
CONCLUSION: Our findings suggest that targeted gene panel sequencing is expected to be the method of choice to improve diagnostic and prognostic accuracy in PKD patients with heterogeneity in genetic background.

Keywords:  Autosomal dominant; Iranian families; Next generation sequencing; PKD1; PKD2; Polycystic kidney disease; Variants

DOI:  https://doi.org/10.34172/aim.2022.95
bioRxiv. 2023 Jul 25. pii: 2023.07.25.550533. [Epub ahead of print]

TTLL12 is required for primary ciliary axoneme formation in polarized epithelial cells.

J Ceglowski, H K Hoffman, K J Hoff, B L McCurdy, J K Moore, R Prekeris.

The primary cilium is a critical sensory organelle that is built of axonemal microtubules ensheathed by a ciliary membrane. In polarized epithelial cells, primary cilia reside on the apical surface and must extend these microtubules directly into the extracellular space and remain a stable structure. However, the factors regulating cross-talk between ciliation and cell polarization, as well as, axonemal microtubule growth and stabilization in polarized epithelia are not fully understood. In this study, we find TTLL12, a previously uncharacterized member of the Tubulin Tyrosine Ligase-Like (TTLL) family, localizes to the base of primary cilia and is required for cilia formation in polarized renal epithelial cells. We also show that TTLL12 directly binds to the α/β-tubulin heterodimer in vitro and regulates microtubule dynamics, stability, and post-translational modifications (PTMs). While all other TTLLs catalyze the addition of glutamate or glycine to microtubule C-terminal tails, TTLL12 uniquely affects tubulin PTMs by promoting both microtubule lysine acetylation and arginine methylation. Together, this work identifies a novel microtubule regulator and provides insight into the requirements for apical extracellular axoneme formation.

DOI: https://doi.org/10.1101/2023.07.25.550533
Zhonghua Kou Qiang Yi Xue Za Zhi. 2023 Aug 03. 58(8): 791-798

[The regulatory role and mechanism of primary cilia in craniofacial and dental development].

Y Sun.

Primary cilia protruding from cell surface are important cell receptors and exist in most types of vertebrate cells. Primary cilia can sense extracellular mechanical signals, chemical signals as well as optical signals, and transduce them into cells, which is crucial for embryonic development and maintenance of tissue homeostasis. Mutations of gene that are responsible for the structure or function of cilia can lead to abnormal cilia signal transport, which in turn leads to ciliopathies. About 30% of ciliopathies are characterized by craniofacial phenotype. The most common cilia-related craniofacial defects include micrognathia, cleft lip, cleft palate, orbital hypertelorism/hypotelorism, flat nasal bridge, prominent forehead, craniosynostosis, and so on, suggesting that primary cilia plays an important role in the normal development of craniofacial development. This review summarizes the key genes involved in the regulation of craniofacial development in primary cilia and the disease phenotypes caused by important cilia gene mutations, in order to provide a reference for understanding the etiology of primary cilia-related craniofacial congenital developmental defects.

DOI: https://doi.org/10.3760/cma.j.cn112144-20230503-00180
Clin Sci (Lond). 2023 Aug 14. 137(15): 1145-1150

Polycystic kidneys: interaction of notch and renin.

Emily A Daniel, Nicole A Sommer, Madhulika Sharma.

  Polycystic kidney disease (PKD) is a developmental disorder, which either manifests in early childhood or later in life, depending on the genetic mutation one harbors. The mechanisms of cyst initiation are not well understood. Increasing literature is now suggesting that Notch signaling may play a critical role in PKD. Activation of Notch signaling is important during nephrogenesis and slows down after development. Deletion of various Notch molecules in the cap mesenchyme leads to formation of cysts and early death in mice. A new study by Belyea et al. has now found that cells of renin lineage may link Notch expression and cystic kidney disease. Here, we use our understanding of Notch signaling and PKD to speculate about the significance of these interactions.

Keywords:  Polycystic kidney disease; notch signalling pathway; renin-angiotensin system

DOI:  https://doi.org/10.1042/CS20230023
Sci Rep. 2023 08 09. 13(1): 12884

Tau tubulin kinase 1 and 2 regulate ciliogenesis and human pluripotent stem cells-derived neural rosettes.

Lucia Binó, Lukáš Čajánek.

Primary cilia are key regulators of embryo development and tissue homeostasis. However, their mechanisms and functions, particularly in the context of human cells, are still unclear. Here, we analyzed the consequences of primary cilia modulation for human pluripotent stem cells (hPSCs) proliferation and differentiation. We report that neither activation of the cilia-associated Hedgehog signaling pathway nor ablation of primary cilia by CRISPR gene editing to knockout Tau Tubulin Kinase 2 (TTBK2), a crucial ciliogenesis regulator, affects the self-renewal of hPSCs. Further, we show that TTBK1, a related kinase without previous links to ciliogenesis, is upregulated during hPSCs-derived neural rosette differentiation. Importantly, we demonstrate that while TTBK1 fails to localize to the mother centriole, it regulates primary cilia formation in the differentiated, but not the undifferentiated hPSCs. Finally, we show that TTBK1/2 and primary cilia are implicated in the regulation of the size of hPSCs-derived neural rosettes.

DOI: https://doi.org/10.1038/s41598-023-39887-9
Hum Mol Genet. 2023 Aug 09. pii: ddad132. [Epub ahead of print]

Defective airway intraflagellar transport underlies a combined motile and primary ciliopathy syndrome caused by IFT74 mutations.

Mahmoud R Fassad, Nisreen Rumman, Katrin Junger, Mitali P Patel, James Thompson, Patricia Goggin, Marius Ueffing, Tina Beyer, Karsten Boldt, Jane S Lucas, Hannah M Mitchison.

Ciliopathies are inherited disorders caused by defective cilia. Mutations affecting motile cilia usually cause the chronic muco-obstructive sinopulmonary disease primary ciliary dyskinesia (PCD) and are associated with laterality defects, while a broad spectrum of early developmental as well as degenerative syndromes arise from mutations affecting signalling of primary (non-motile) cilia. Cilia assembly and functioning requires intraflagellar transport of cargos assisted by IFT-B and IFT-A adaptor complexes. Within IFT-B, the N-termini of partner proteins IFT74 and IFT81 govern tubulin transport to build the ciliary microtubular cytoskeleton. We detected a homozygous 3 kb intragenic IFT74 deletion removing the exon 2 initiation codon and 40 N-terminal amino acids in two affected siblings. Both had clinical features of PCD with bronchiectasis, but no laterality defects. They also had retinal dysplasia and abnormal bone growth, with a narrowed thorax and short ribs, shortened long bones and digits and abnormal skull shape. This resembles short-rib thoracic dysplasia, a skeletal ciliopathy previously linked to IFT defects in primary cilia, not motile cilia. Ciliated nasal epithelial cells collected from affected individuals had reduced numbers of shortened motile cilia with disarranged microtubules, some mis-orientation of the basal feet, and disrupted cilia structural and IFT protein distributions. No full length IFT74 was expressed, only truncated forms that were consistent with N-terminal deletion and inframe translation from downstream initiation codons. In affinity purification mass spectrometry, exon 2-deleted IFT74 initiated from the nearest inframe downstream methionine 41 still interacts as part of the IFT-B complex, but only with reduced interaction levels and not with all its usual IFT-B partners. We propose that this is a hypomorphic mutation with some residual protein function retained, that gives rise to a non-lethal primary skeletal ciliopathy combined with defective motile cilia and PCD.

DOI: https://doi.org/10.1093/hmg/ddad132
Semin Nephrol. 2023 Aug 03. pii: S0270-9295(23)00115-8. [Epub ahead of print]43(2): 151405

Diet and Polycystic Kidney Disease: Nutrients, Foods, Dietary Patterns, and Implications for Practice.

Kelly Lambert, Robert Gardos, Helen Coolican, Lauren Pickel, Hoon-Ki Sung, Angela Yee-Moon Wang, Albert Cm Ong.

  Polycystic kidney disease (PKD) is a chronic, progressive hereditary condition characterized by abnormal development and growth of cysts in the kidneys and other organs. There is increasing interest in exploring whether dietary modifications may prevent or slow the disease course in people with PKD. Although vasopressin-receptor agonists have emerged as a novel drug treatment in advancing care for people with PKD, several recent landmark trials and clinical discoveries also have provided new insights into potential dietary-related therapeutic strategies. In this review, we summarize the current evidence pertaining to nutrients, foods, dietary patterns, cyst growth, and progression of PKD. We also describe existing evidence-based dietary care for people with PKD and outline the potential implications for advancing evidence-based dietary interventions. Semin Nephrol 43:x-xx © 2023 Elsevier Inc. All rights reserved.

Keywords:  Polycystic kidney disease; diet; dietary patterns; food; nutrients; nutrition

DOI:  https://doi.org/10.1016/j.semnephrol.2023.151405
bioRxiv. 2023 Jul 25. pii: 2023.07.25.550535. [Epub ahead of print]

Novel centriolar defects underlie a primary ciliary dyskinesia phenotype in an adenylate kinase 7 deficient ciliated epithelium.

Jennifer Sheridan, Aline Grata, Eve E Suva, Enzo Bresteau, Linus R Mitchell, Osama Hassan, Brian Mitchell.

The skin of Xenopus embryos contains numerous multiciliated cells (MCCs), which collectively generate a directed fluid flow across the epithelial surface essential for distributing the overlaying mucous. MCCs develop into highly specialized cells to generate this flow, containing approximately 150 evenly spaced centrioles that give rise to motile cilia. MCC-driven fluid flow can be impaired when ciliary dysfunction occurs, resulting in primary ciliary dyskinesia (PCD) in humans. Mutations in a large number of genes (∼50) have been found to be causative to PCD. Recently, studies have linked low levels of Adenylate Kinase 7 (AK7) gene expression to patients with PCD; however, the mechanism for this link remains unclear. Additionally, AK7 mutations have been linked to multiple PCD patients. Adenylate kinases modulate ATP production and consumption, with AK7 explicitly associated with motile cilia. Here we reproduce an AK7 PCD-like phenotype in Xenopus and describe the cellular consequences that occur with manipulation of AK7 levels. We show that AK7 localizes throughout the cilia in a DPY30 domain-dependent manner, suggesting a ciliary function. Additionally, we find that AK7 overexpression increases centriole number, suggesting a role in regulating centriole biogenesis. We find that in AK7-depleted embryos, cilia number, length, and beat frequency are all reduced, which in turn, significantly decreases the tissue-wide mucociliary flow. Additionally, we find a decrease in centriole number and an increase in sub-apical centrioles, implying that AK7 influences both centriole biogenesis and docking, which we propose underlie its defect in ciliogenesis. We propose that AK7 plays a role in PCD by impacting centriole biogenesis and apical docking, ultimately leading to ciliogenesis defects that impair mucociliary clearance.

DOI: https://doi.org/10.1101/2023.07.25.550535
Kidney Int Rep. 2023 Aug;8(8): 1616-1626

Interaction Between Determinants Governing Urine Volume in Patients With ADPKD on Tolvaptan and its Impact on Quality of Life.

Polina Todorova, Sita Arjune, Claudia Hendrix, Simon Oehm, Johannes Schmidt, Denise Krauß, Katharina Burkert, Volker Rolf Burst, Thomas Benzing, Volker Boehm, Franziska Grundmann, Roman-Ulrich Müller.

   Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic cause of kidney failure. Tolvaptan, a vasopressin 2 receptor antagonist, is the first drug with proven disease-modifying activity. Long-term treatment adherence is crucial, but a considerable fraction of patients discontinue treatment, because of aquaretic side effects.
Methods: Twenty-four-hour urine was collected in 75 patients with ADPKD during up-titration of tolvaptan and, in combination with clinical characteristics, examined to identify factors influencing urine volume. Patient-reported outcomes were analyzed using the Short Form-12 (SF-12) and patient-reported outcomes questionnaires reporting micturition frequency and burden of urine volume.
Results: Initiation of therapy led to a large increase in urine volume followed by only minor further increase during up-dosing. Younger patients and patients with better kidney function experienced a larger relative rise. Twenty-four-hour urine osmolality dropped by about 50% after therapy initiation independently of dose, with a considerable proportion of patients achieving adequate suppression. Sodium and potassium intake turned out to be the only significant modifiable factors for urine volume after multivariate linear regression models, whereas age and weight could be identified as non-modifiable factors. No change in quality of life (QoL) was detected in relation to treatment or urine volume using SF-12 questionnaires, a finding that was further supported by the results of the patient-reported outcomes assessment.
Conclusion: This study provides an in-detail analysis of factors associated with the degree of polyuria on tolvaptan and puts them into the context of QoL. These findings will contribute to optimized patient counseling regarding this treatment option in ADPKD.

Keywords:  ADPKD; dose; osmolality; quality of life; tolvaptan; urine volume

DOI:  https://doi.org/10.1016/j.ekir.2023.05.011
J Cell Physiol. 2023 Aug 10.

Primary cilia: Structure, dynamics, and roles in cancer cells and tumor microenvironment.

Yi-Ting Guan, Chong Zhang, Hong-Yong Zhang, Wen-Lu Wei, Wei Yue, Wei Zhao, Dong-Hui Zhang.

  Despite the initiation of tumor arises from tumorigenic transformation signaling in cancer cells, cancer cell survival, invasion, and metastasis also require a dynamic and reciprocal association with extracellular signaling from tumor microenvironment (TME). Primary cilia are the antenna-like structure that mediate signaling sensation and transduction in different tissues and cells. Recent studies have started to uncover that the heterogeneous ciliation in cancer cells and cells from the TME in tumor growth impels asymmetric paracellular signaling in the TME, indicating the essential functions of primary cilia in homeostasis maintenance of both cancer cells and the TME. In this review, we discussed recent advances in the structure and assembly of primary cilia, and the role of primary cilia in tumor and TME formation, as well as the therapeutic potentials that target ciliary dynamics and signaling from the cells in different tumors and the TME.

Keywords:  cancer; cell death; immune system; primary cilia; tumor; tumor microenvironment (TME)

DOI:  https://doi.org/10.1002/jcp.31092
Int J Biol Sci. 2023 ;19(12): 3726-3743

Broadening horizons: the multifaceted functions of ferroptosis in kidney diseases.

Qi Feng, Yang Yang, Kaidi Ren, Yingjin Qiao, Zhi Sun, Shaokang Pan, Fengxun Liu, Yong Liu, Jinling Huo, Dongwei Liu, Zhangsuo Liu.

  Ferroptosis is an iron-dependent programmed cell death pattern that is characterized by iron overload, reactive oxygen species (ROS) accumulation and lipid peroxidation. Growing viewpoints support that the imbalance of iron homeostasis and the disturbance of lipid metabolism contribute to tissue or organ injury in various kidney diseases by triggering ferroptosis. At present, the key regulators and complicated network mechanisms associated with ferroptosis have been deeply studied; however, its role in the initiation and progression of kidney diseases has not been fully revealed. Herein, we aim to discuss the features, key regulators and complicated network mechanisms associated with ferroptosis, explore the emerging roles of organelles in ferroptosis, gather its pharmacological progress, and systematically summarize the most recent discoveries about the crosstalk between ferroptosis and kidney diseases, including renal cell carcinoma (RCC), acute kidney injury (AKI), diabetic kidney disease (DKD), autosomal dominant polycystic kidney disease (ADPKD), renal fibrosis, lupus nephritis (LN) and IgA nephropathy. We further conclude the potential therapeutic strategies by targeting ferroptosis for the prevention and treatment of kidney diseases and hope that this work will provide insight for the further study of ferroptosis in the pathogenesis of kidney-related diseases.

Keywords:  ferroptosis; kidney diseases; molecular mechanism; pharmacological progress

DOI:  https://doi.org/10.7150/ijbs.85674