bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2023–07–23
fiveteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Oral-facial-digital syndrome type 1: the kidney cystic disease that mimics autosomal dominant polycystic kidney disease.
  2. Specific nutritional strategy is needed for good nutritional status in autosomal dominant polycystic kidney disease.
  3. [Application of single-sperm sequencing technology in preimplantation genetic testing for men with autosomal dominant polycystic kidney disease].
  4. A direct interaction between CENTLEIN and RABIN8 is required for primary cilium formation.
  5. Autosomal dominant polycystic kidney disease in Colombia.
  6. Function follows form: the quest for the best prognostic imaging biomarker in ADPKD.
  7. Identified eleven exon variants in PKD1 and PKD2 genes that altered RNA splicing by minigene assay.
  8. Functions of actin-binding proteins in cilia structure remodeling and signalling.
  9. Modulation of inner junction proteins contributes to axoneme differentiation.
  10. Intracranial arachnoid cysts.
  11. From Primary Cilia and Planar Cell Polarity to Kidney Injury and Repair.
  12. [Primary ciliary dyskinesia complicated by male infertility: An update].
  13. A novel PKHD1 splicing variant identified in a fetus with autosomal recessive polycystic kidney disease.
  14. Organization, functions, and mechanisms of the BBSome in development, ciliopathies, and beyond.
  15. Deciphering Rho-associated, coiled-coil-containing protein kinase in diabetic nephropathy: small steps towards a giant leap.
  1. Kidney Int. 2023 Aug;pii: S0085-2538(23)00162-X. [Epub ahead of print]104(2): 399
    Oral-facial-digital syndrome type 1: the kidney cystic disease that mimics autosomal dominant polycystic kidney disease.
    Leanna Ritchie, Roaa Zayat, Fouad T Chebib.
      
    DOI:  https://doi.org/10.1016/j.kint.2023.03.002
  2. J Ren Nutr. 2023 Jul 19. pii: S1051-2276(23)00109-7. [Epub ahead of print]
    Specific nutritional strategy is needed for good nutritional status in autosomal dominant polycystic kidney disease.
    Xue Cheng, Liming Zhang, Shuqin Mei, Xu Jing, Zhiguo Mao.
      
    DOI:  https://doi.org/10.1053/j.jrn.2023.05.010
  3. Zhonghua Nan Ke Xue. 2022 May;28(5): 408-414
    [Application of single-sperm sequencing technology in preimplantation genetic testing for men with autosomal dominant polycystic kidney disease].
    Tian-Qin Deng, Yu-Li Xie, Hua-Kun Zhang, Hai-Yan Chen, Shu-Jing Jiao, Xue-Mei Li.
       OBJECTIVE: To investigate the value of single-sperm sequencing technology in preimplantation genetic testing.
    METHODS: Haplotypes were constructed by single-sperm isolation combined with single-sperm sequencing for a patient with autosomal dominant polycystic kidney disease (ADPKD) caused by de novo mutation of the PKD1 gene c.3815T>G. 50. Single-sperm samples were isolated by mechanical braking, whole-genome amplification was performed, and mutation loci and their 187 upstream and downstream single nucleotide polymorphisms (SNP) were designed. The amplified products were verified for determination of the chromosome haplotypes carrying or not carrying pathogenic mutations. The embryos carrying pathogenic mutations were identified in 7 embryonic trophectoderm cell biopsy samples by high-throughput sequencing after whole-genome amplification. Available blastocysts were selected for embryo transfer, and amniotic fluid samples were collected at 18 weeks of gestation to determine whether the fetuses carried pathogenic mutations.
    RESULTS: A total of 30 SNPs were identified by single-sperm sequencing, and haplotypes were successfully constructed. Preimplantation haplotype analysis indicated that 5 embryos carried pathogenic mutations and 2 did not. mid-gestation amniotic fluid genetic testing revealed no PKD1 gene c.3815T>G mutation in the fetuses.
    CONCLUSION: SNPs can be identified by single-sperm sequencing in males carrying de novo pathogenic mutation, and haplotypes can be constructed by linkage analysis for preimplantation genetic testing of embryos.
    Keywords:   autosomal dominant polycystic kidney disease; preimplantation genetic testing; single-sperm sequencing
  4. Acta Biochim Biophys Sin (Shanghai). 2023 Jul 20.
    A direct interaction between CENTLEIN and RABIN8 is required for primary cilium formation.
    Liansheng Li, Junlin Li, Li Yuan.
      Primary cilia are formed in nearly all growth-arrested cells and are essential for mammalian development and tissue homeostasis. Defects in primary cilia result in a range of disorders in humans, named ciliopathies. The spatiotemporal localization of RABIN8 on the pericentrosome is an early step in ciliogenesis. Here, we show that CENTLEIN depletion causes the persistent accumulation of RABIN8 on the pericentrosome and primary cilium loss in hTERT-immortalized retinal pigment epithelial cells and murine embryonic fibroblasts. CENTLEIN interacts with RABIN8 directly. A stretch of a 31-amino acid sequence located in the 200‒230 region of the RABIN8 GEF domain is responsible for its physical interaction with CENTLEIN, while expression of the full-length but not the internal deletion lacking the RABIN8-binding site of CENTLEIN largely rescues the ciliogenesis defect provoked by CENTLEIN depletion. Expression of activated RAB8A partially reverses cilium loss in CENTLEIN-null RPE1 cells, so the functional importance of the CENTLEIN-RABIN8 interaction is defined.
    Keywords:  CENTLEIN; CENTLEIN-RABIN8 interaction; RABIN8; pericentrosomal RABIN8; primary cilia
    DOI:  https://doi.org/10.3724/abbs.2023064
  5. BMC Nephrol. 2023 07 17. 24(1): 211
    Autosomal dominant polycystic kidney disease in Colombia.
    Jessica T Camargo, Camilo A González, Lina Herrera, Nancy Yomayusa-González, Milciades Ibañez, Ana M Valbuena-García, Lizbeth Acuña-Merchán.
       BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of chronic kidney disease (CKD) that requires dialysis. Knowing geographical clusters can be critical for early diagnosis, progression control, and genetic counseling. The objective was to establish the prevalence, geographic location, and ethnic groups of patients with ADPKD who underwent dialysis or kidney transplant in Colombia between 2015 and 2019.
    METHODS: We did a cross-sectional study with data from the National Registry of Chronic Kidney Disease (NRCKD) managed by the High-Cost Diseases Fund (Cuenta de Alto Costo [CAC] in Spanish) between July 1, 2015, and June 30, 2019. We included Colombian population with CKD with or without renal replacement therapy (RRT) due to ADPKD. Crude and adjusted prevalence rates were estimated by state and city.
    RESULTS: 3,339 patients with ADPKD were included, period prevalence was 9.81 per 100,000 population; there were 4.35 cases of RRT per 100,000 population, mean age of 52.58 years (± 13.21), and 52.78% women. Seventy-six patients were Afro-Colombians, six were indigenous, and one Roma people. A total of 46.07% began scheduled dialysis. The highest adjusted prevalence rate was in Valle del Cauca (6.55 cases per 100,000 population), followed by Risaralda, and La Guajira. Regarding cities, Cali had the highest prevalence rate (9.38 cases per 100,000 population), followed by Pasto, Medellin, and Bucaramanga.
    CONCLUSIONS: ADPKD prevalence is lower compared to Europe and US; some states with higher prevalence could be objective to genetic prevalence study.
    Keywords:  Chronic kidney failure; Dialysis; Kidney transplant; Polycystic kidney disease; Renal replacement therapy
    DOI:  https://doi.org/10.1186/s12882-023-03266-3
  6. Kidney Int. 2023 Aug;pii: S0085-2538(23)00409-X. [Epub ahead of print]104(2): 239-241
    Function follows form: the quest for the best prognostic imaging biomarker in ADPKD.
    Andreas D Kistler.
      Total kidney volume represents the most solid prognostic biomarker for autosomal dominant polycystic kidney disease, because it mirrors cyst growth that precedes kidney function decline. Considerable variability of glomerular filtration rate trajectories, however, remains unexplained by total kidney volume, and its calculation is time-consuming. Using deep learning algorithms, Gregory et al. determined total kidney volume and other, novel, imaging-based biomarkers. They achieved automation and improved prognostic accuracy for long-term kidney function loss, yet the study leaves some open questions and room for further improvement.
    DOI:  https://doi.org/10.1016/j.kint.2023.05.023
  7. BMC Genomics. 2023 Jul 19. 24(1): 407
    Identified eleven exon variants in PKD1 and PKD2 genes that altered RNA splicing by minigene assay.
    Xuyan Liu, Xiaomeng Shi, Qing Xin, Zhiying Liu, Fengjiao Pan, Dan Qiao, Mengke Chen, Yiyin Zhang, Wencong Guo, Changying Li, Yan Zhang, Leping Shao, Ruixiao Zhang.
       BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic multisystem disease caused primarily by mutations in the PKD1 gene or PKD2 gene. There is increasing evidence that some of these variants, which are described as missense, synonymous or nonsense mutations in the literature or databases, may be deleterious by affecting the pre-mRNA splicing process.
    RESULTS: This study aimed to determine the effect of these PKD1 and PKD2 variants on exon splicing combined with predictive bioinformatics tools and minigene assay. As a result, among the 19 candidate single nucleotide alterations, 11 variants distributed in PKD1 (c.7866C > A, c.7960A > G, c.7979A > T, c.7987C > T, c.11248C > G, c.11251C > T, c.11257C > G, c.11257C > T, c.11346C > T, and c.11393C > G) and PKD2 (c.1480G > T) were identified to result in exon skipping.
    CONCLUSIONS: We confirmed that 11 variants in the gene of PKD1 and PKD2 affect normal splicing by interfering the recognition of classical splicing sites or by disrupting exon splicing enhancers and generating exon splicing silencers. This is the most comprehensive study to date on pre-mRNA splicing of exonic variants in ADPKD-associated disease-causing genes in consideration of the increasing number of identified variants in PKD1 and PKD2 gene in recent years. These results emphasize the significance of assessing the effect of exon single nucleotide variants in ADPKD at the mRNA level.
    Keywords:  Exon skipping; Exonic variant; Minigene assay; PKD1; PKD2; pre-mRNA splicing
    DOI:  https://doi.org/10.1186/s12864-023-09444-9
  8. Biol Cell. 2023 Jul 21.
    Functions of actin-binding proteins in cilia structure remodeling and signalling.
    Siqi Wang, Xin Wang, Congbin Pan, Ying Liu, Min Lei, Xiying Guo, Qingjie Chen, Xiaosong Yang, Changhan Ouyang, Zhanhong Ren.
      Cilia are microtubule-based organelles found on the surfaces of many types of cells, including cardiac fibroblasts, vascular endothelial cells, human retinal pigmented epithelial-1 (RPE-1) cells and alveolar epithelial cells. These organelles can be classified as immotile cilia, referred to as primary cilia in mammalian cells, and motile cilia. Primary cilia are cellular sensors that detect extracellular signals; this is a critical function associated with ciliopathies, which are characterized by the typical clinical features of developmental disorders. Cilia are extensively studied organelles of the microtubule cytoskeleton. However, the ciliary actin cytoskeleton has rarely been studied. Clear evidence has shown that highly regulated actin cytoskeleton dynamics contribute to normal ciliary function. Actin-binding proteins (ABPs) play vital roles in filamentous actin (F-actin) morphology. Here, we discuss recent progress in understanding the roles of ABPs in ciliary structural remodeling and further downstream ciliary signalling with a focus on the molecular mechanisms underlying actin cytoskeleton-related ciliopathies. This article is protected by copyright. All rights reserved.
    Keywords:  actin cytoskeleton; cilia; ciliogenesis; signalling pathway
    DOI:  https://doi.org/10.1111/boc.202300026
  9. Proc Natl Acad Sci U S A. 2023 07 25. 120(30): e2303955120
    Modulation of inner junction proteins contributes to axoneme differentiation.
    Zhe Chen, Ming Li, Hao Zhu, Guangshuo Ou.
      Cilia build distinct subdomains with variable axonemal structures to perform diverse functions in cell motility and signaling. In sensory cilia across species, an axoneme differentiates longitudinally into a middle segment with nine microtubule (MT) doublets and a distal segment with nine MT singlets that extends from the A tubules of the doublets. Here, we study axoneme differentiation in Caenorhabditis elegans by analyzing the flagellar inner junction protein FAP20 and PCRG1 that connect A and B tubules in Chlamydomonas. The nematode CFAP-20 is restricted to the middle segment with doublets, and its loss disconnects A and B tubules. However, PCRG-1 is absent from most sensory cilia, and its deletion does not disrupt cilia. Ectopic introduction of PCRG-1 into cilia generated abnormal MT doublets in the distal segment and reduced intraflagellar transport and animal sensation. Thus, the absence of an inner junction protein prevents B-tubule extension, which contributes to axoneme differentiation and ciliary function.
    Keywords:  axoneme differentiation; cilia; inner junction protein; microtubules
    DOI:  https://doi.org/10.1073/pnas.2303955120
  10. Childs Nerv Syst. 2023 Jul 19.
    Intracranial arachnoid cysts.
    A Karim Ahmed, Alan R Cohen.
       PURPOSE: The purpose of this review article is to outline the natural history, pathogenesis, anatomic considerations and surgical decision-making in caring for patients with intracranial arachnoid cysts.
    METHODS: A review of the literature for intracranial arachnoid cysts was performed using Embase, PubMed, and Web of Science databases, including review of the bibliographies of eligible articles and the author's own experience.
    RESULTS: Among those reviewed, 59 relevant original articles were included as well as illustrative cases from the authors own experience.
    CONCLUSIONS: Arachnoid cysts are congenital lesions characterized by split arachnoid membrane, thick collagen in the cyst wall, absent traversing trabecular processes within the cyst, and hyperplastic arachnoid cells in the cyst wall. The underlying etiology is not entirely known, and they occur in greater proportion in males and in greater incidence with various genetic conditions including Down syndrome, mucopolysaccharidosis, schizencephaly, neurofibromatosis, autosomal dominant polycystic kidney disease (ADPKD), acrocallosal syndrome, and Aicardi syndrome. Most intracranial arachnoid cysts are incidentally found and occur in the middle cranial fossa, with the remaining occurring in the cerebellopontine angle, suprasellar cistern, quadrigeminal cistern, convexity, and posterior fossa/cisterna magna. The current article outlines the natural history, prevalence, demographic factors, and treatment decisions in managing patients with intracranial arachnoid cysts.
    Keywords:  Arachnoid cyst; Interhemispheric cyst; Middle fossa cyst; Posterior fossa cyst; Quadrigeminal cyst; Retrocerebellar cyst; Suprasellar cyst
    DOI:  https://doi.org/10.1007/s00381-023-06066-0
  11. Nephron. 2023 Jul 17. 1
    From Primary Cilia and Planar Cell Polarity to Kidney Injury and Repair.
    Shixuan Wang, Jinghua Hu, Zheng Dong.
      Almost every cell in the kidney, including renal tubular epithelial cells, has a primary cilium, which is a membrane-bound, hair-like structure protruding from the cellular surface. Dysfunction of primary cilia has been linked to a wide spectrum of human genetic diseases, termed ciliopathies. Planar cell polarity (PCP) refers to the coordinated alignment of cells along the cell sheet or tissue plane, a fundamental process in embryo development and organogenesis. Interestingly, there is evidence that primary cilium and PCP are interconnected. However, very limited is known about the involvement of cilia and PCP in kidney injury and repair. By using cell and mouse models, we have demonstrated a protective role of primary cilia in acute kidney injury. Mechanistically, we unveiled a reciprocal promoting relationship between cilia and autophagy in kidney tubular cells, and, accordingly, cilia may protect tubular cells by enhancing autophagy. Our recent studies further demonstrated that PCP dysfunction exaggerates acute kidney injury and may also contribute to maladaptive kidney repair after acute kidney injury. These findings provide a novel dimension to further understanding kidney injury and repair from the standpoint of cell biology.
    Keywords:  Acute renal injury; Chronic renal disease; Cilia; Fibrosis; Planar cell polarity
    DOI:  https://doi.org/10.1159/000531294
  12. Zhonghua Nan Ke Xue. 2021 Dec;27(12): 1124-1128
    [Primary ciliary dyskinesia complicated by male infertility: An update].
    Zhuo Yin, Jin-Rui Yang.
      Primary ciliary dyskinesia (PCD) is an autosomal recessive genetic disease. Gene mutation leads to ciliary structural abnormalities or functional defects, resulting in respiratory diseases. Male patients with PCD are prone to infertility, which pathogenically may be attributed to gene mutation-induced dysfunction of respiratory cilia and sperm flagella. This reviews focuses on the research progress in microtubule structure, gene mutation and outcomes of assisted reproduction relating to PCD complicated by male infertility.
    Keywords:   assisted reproduction ; gene; male infertility; primary ciliary dyskinesia
  13. Front Genet. 2023 ;14 1207772
    A novel PKHD1 splicing variant identified in a fetus with autosomal recessive polycystic kidney disease.
    Mingzhu Miao, Liqun Feng, Jue Wang, Cheng Xu, Xiaotian Su, Guoying Zhang, Shoulian Lu.
      Objective: Variants of the polycystic kidney and hepatic disease 1 (PKHD1) gene are associated with autosomal recessive polycystic kidney disease (ARPKD). This study aimed to identify the genetic causes in a Chinese pedigree with ARPKD and design a minigene construct of the PKHD1 gene to investigate the impact of its variants on splicing. Methods: Umbilical cord samples from the proband and peripheral blood samples from his parents were collected, and genomic DNA was extracted for whole-exome sequencing (WES). Bioinformatic analysis was used to identify potential genetic causes, and Sanger sequencing confirmed the existence of variants within the pedigree. A minigene assay was performed to validate the effects of an intronic variant on mRNA splicing. Results: Two variants, c.9455del (p.N3152Tfs*10) and c.2408-13C>G, were identified in the PKHD1 gene (NM_138694.4) by WES; the latter has not been previously reported. In silico analysis predicted that this intronic variant is potentially pathogenic. Bioinformatic splice prediction tools revealed that the variant is likely to strongly impact splice site function. An in vitro minigene assay revealed that c.2408-13C>G can cause aberrant splicing, resulting in the retention of 12 bp of intron 23. Conclusion: A novel pathogenic variant of PKHD1, c.2408-13C>G, was found in a fetus with ARPKD, which enriches the variant spectrum of the PKHD1 gene and provides a basis for genetic counseling and the diagnosis of ARPKD. Minigenes are optimal to determine whether intron variants can cause aberrant splicing.
    Keywords:  PKHD1; aberrant splicing; autosomal recessive polycystic kidney disease; intronic variant; minigene; whole-exome sequencing
    DOI:  https://doi.org/10.3389/fgene.2023.1207772
  14. Elife. 2023 07 19. pii: e87623. [Epub ahead of print]12
    Organization, functions, and mechanisms of the BBSome in development, ciliopathies, and beyond.
    Xiaoyu Tian, Huijie Zhao, Jun Zhou.
      The BBSome is an octameric protein complex that regulates ciliary transport and signaling. Mutations in BBSome subunits are closely associated with ciliary defects and lead to ciliopathies, notably Bardet-Biedl syndrome. Over the past few years, there has been significant progress in elucidating the molecular organization and functions of the BBSome complex. An improved understanding of BBSome-mediated biological events and molecular mechanisms is expected to help advance the development of diagnostic and therapeutic approaches for BBSome-related diseases. Here, we review the current literature on the structural assembly, transport regulation, and molecular functions of the BBSome, emphasizing its roles in cilium-related processes. We also provide perspectives on the pathological role of the BBSome in ciliopathies as well as how these can be exploited for therapeutic benefit.
    Keywords:  BBSome; Cilia; cell biology; ciliopathy; cytoskeleton
    DOI:  https://doi.org/10.7554/eLife.87623
  15. Endocr J. 2023 Jul 20.
    Deciphering Rho-associated, coiled-coil-containing protein kinase in diabetic nephropathy: small steps towards a giant leap.
    Keiichiro Matoba.
      Diabetic nephropathy is a public health problem worldwide. Our understanding of the molecular machinery, as well as the clinical therapies for diabetic nephropathy, has evolved dramatically in recent years. However, even with this progress, there are residual risks of kidney failure and cardiovascular events in patients with diabetes. Rho-associated, coiled-coil-containing protein kinase (ROCK) is activated in response to various pathologic stimuli in the context of diabetes. The contribution of ROCK has been investigated in vivo using gene deletion rodent models and specific inhibitors, which are providing key insights into the pathologic function of ROCK in diabetic nephropathy. ROCK has two isoforms, ROCK1 and ROCK2. Both isoforms are expressed in the kidney, including mesangial cells, podocytes, and endothelial cells. ROCK1 blunts AMP-activated protein kinase (AMPK), while ROCK2 negatively regulates peroxisome proliferator-activated receptor α (PPARα) to inhibit fatty acid oxidation, both of which lead to structural and functional impairment of glomeruli in diabetes. Of note, ROCK signaling is activated in the kidney of animal models and patients with diabetes. In addition, an observational study has shown that fasudil hydrochloride, an ATP-competitive selective ROCK inhibitor, significantly attenuated proteinuria among patients with diabetes. These findings highlight the promising prospects for the development of a ROCK-centered approach against the progression of diabetic nephropathy.
    Keywords:  Chronic kidney disease; Diabetes; Diabetic nephropathy; Rho-associated, coiled-coil-containing protein kinase (ROCK)
    DOI:  https://doi.org/10.1507/endocrj.EJ23-0282
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