PubMed Latest Articles

20 April 2021

• Liver transplantation for congenital hepatic fibrosis
  Congenital hepatic fibrosis (CHF) is a hereditary fibrocystic disease that can progress to portal hypertension and recurrent cholangitis requiring liver transplantation (LT). It can be associated with renal pathology and need for kidney transplantation (KT). We describe the clinical characteristics and outcomes of patients undergoing liver transplantation alone (LTA) and simultaneous liver-kidney transplantation (SLKT) for CHF using the Unites States Scientific Registry of Transplant Recipients....
• High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses
  Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel...
• Non-redundant roles of DIAPHs in primary ciliogenesis
  Primary cilia are hubs for several signaling pathways, and disruption in cilia function and formation leads to a range of diseases collectively known as ciliopathies. Both ciliogenesis and cilia maintenance depend on vesicle trafficking along a network of microtubules and actin filaments toward the basal body. The DIAPH (Diaphanous-related) family of formins promote both actin polymerization and microtubule (MT) stability. Recently, we showed that the formin DIAPH1 is involved in ciliogenesis....
• Moonlighting of mitotic regulators in cilium disassembly
  Correct timing of cellular processes is essential during embryological development and to maintain the balance between healthy proliferation and tumour formation. Assembly and disassembly of the primary cilium, the cell's sensory signalling organelle, are linked to cell cycle timing in the same manner as spindle pole assembly and chromosome segregation. Mitotic processes, ciliary assembly, and ciliary disassembly depend on the centrioles as microtubule-organizing centres (MTOC) to regulate...
• CDKL kinase regulates the length of the ciliary proximal segment
  Cilia are organelles found throughout most unicellular eukaryotes and different metazoan cell types. To accomplish their essential roles in cell motility, fluid flow, and signaling, cilia are divided into subcompartments with variable structures, compositions, and functions. How these specific subcompartments are built remains almost completely unexplored. Here, we show that C. elegans CDKL-1, related to the human CDKL kinase family (CDKL1/CDKL2/CDKL3/CDKL4/CDKL5), specifically controls the...
• Time-resolved proteomics profiling of the ciliary Hedgehog response
  The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid, and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we...
• The BBSome: a nexus controlling energy metabolism in the brain
  Bardet-Biedl syndrome (BBS) is a syndromic ciliopathy that has obesity as a cardinal feature. BBS is caused by mutations in BBS genes. BBS proteins control primary cilia function, and BBS mutations therefore lead to dysfunctional primary cilia. Obesity in patients with BBS is mainly caused by hyperphagia due to dysregulated neuronal function in the brain, in particular in the hypothalamus. However, the mechanism by which mutations in BBS genes result in dysfunction in hypothalamic neurons is not...
• Renal Squamous Cell Carcinoma-related Polymyositis in a Patient with Autosomal Dominant Polycystic Kidney Disease
  A 74-year-old Japanese woman diagnosed with autosomal dominant polycystic kidney disease (ADPKD) was admitted to our institute for the further examination of right-side groin pain developing in the past week. The patient was diagnosed with polymyositis (PM). Diagnostic imaging showed a mass lesion measuring 8 cm and a renal stone in the right kidney. Immediately following surgical resection of the right kidney, the patient's serum CK decreased to the normal range. A histopathological analysis...
• A ZFYVE19 gene mutation associated with neonatal cholestasis and cilia dysfunction: case report with a novel pathogenic variant
  CONCLUSIONS: Our findings are consistent with and expands the recent evidence linking ZFYVE19 to a novel, likely non-syndromic, high GGT-PFIC phenotype with neonatal onset. Due to the possible role of ZFYVE19 in cilia function and the unprecedented coexistence of a coincidental hereditary sterol disorder in our case, continuous monitoring will be necessary to substantiate type of liver disease progression and/or possible emergence of a multisystemic involvement. What mentioned above confirms...
• Primary cilia and the DNA damage response: linking a cellular antenna and nuclear signals
  The maintenance of genome stability involves integrated biochemical activities that detect DNA damage or incomplete replication, delay the cell cycle, and direct DNA repair activities on the affected chromatin. These processes, collectively termed the DNA damage response (DDR), are crucial for cell survival and to avoid disease, particularly cancer. Recent work has highlighted links between the DDR and the primary cilium, an antenna-like, microtubule-based signalling structure that extends from...
• A rare triad of morning glory disc anomaly, moyamoya vasculopathy, and transsphenoidal cephalocele: pathophysiological considerations and surgical management
  Morning glory disc anomaly is a congenital abnormality of the optic disc and peripapillary retina reported as an isolated condition or associated with various anomalies, including basal encephaloceles and moyamoya vasculopathy. However, the co-occurrence of these three entities is extremely rare and the pathogenesis is still poorly understood. Moreover, data on the surgical management and long-term follow-up of the intracranial anomalies are scarce. Here, we describe the case of a 11-year-old...
• Fibrocystic liver disease: novel concepts and translational perspectives
  Fibrocystic liver diseases (FLDs) comprise a heterogeneous group of rare diseases of the biliary tree, having in common an abnormal development of the embryonic ductal plate caused by genetically-determined dysfunctions of proteins expressed in the primary cilia of cholangiocytes (and therefore grouped among the "ciliopathies"). The ductal dysgenesis may affect the biliary system at multiple levels, from the small intrahepatic bile ducts [congenital hepatic fibrosis (CHF)], to the larger...
• Mutation in the Ciliary Protein C2CD3 Reveals Organ-Specific Mechanisms of Hedgehog Signal Transduction in Avian Embryos
  Primary cilia are ubiquitous microtubule-based organelles that serve as signaling hubs for numerous developmental pathways, most notably the Hedgehog (Hh) pathway. Defects in the structure or function of primary cilia result in a class of diseases called ciliopathies. It is well known that primary cilia participate in transducing a Hh signal, and as such ciliopathies frequently present with phenotypes indicative of aberrant Hh function. Interestingly, the exact mechanisms of cilia-dependent Hh...
• Investigating Primary Cilia during Peripheral Nervous System Formation
  The primary cilium plays a pivotal role during the embryonic development of vertebrates. It acts as a somatic signaling hub for specific pathways, such as Sonic Hedgehog signaling. In humans, mutations in genes that cause dysregulation of ciliogenesis or ciliary function lead to severe developmental disorders called ciliopathies. Beyond its role in early morphogenesis, growing evidence points towards an essential function of the primary cilium in neural circuit formation in the central nervous...
• Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report
  Leber congenital amaurosis due to CEP290 ciliopathy is being explored by treatment with the antisense oligonucleotide (AON) sepofarsen. One patient who was part of a larger cohort (ClinicalTrials.gov NCT03140969 ) was studied for 15 months after a single intravitreal sepofarsen injection. Concordant measures of visual function and retinal structure reached a substantial efficacy peak near 3 months after injection. At 15 months, there was sustained efficacy, even though there was evidence of...
• Non-classic splicing mutation in the CPLANE1 (C5orf42) gene cause Joubert syndrome in a fetus with severe craniocerebral dysplasia
  CONCLUSION: The cerebellum dysplasia fetus without obvious molar tooth sign was finally diagnosed as Joubert syndrome, combined with the results from genetic detecting and the postnatal clinical symptoms. We also highlight the clinical heterogeneity of encephalodysplasia in Joubert syndrome which increases the difficulty of clinical diagnosis especially for prenatal diagnosis. Our findings provides a new perspective for the prenatal diagnosis of Joubert syndrome with severe craniocerebral...
• alms1 mutant zebrafish do not show hair cell phenotypes seen in other cilia mutants
  Multiple cilia-associated genes have been shown to affect hair cells in zebrafish (Danio rerio), including the human deafness gene dcdc2, the radial spoke gene rsph9, and multiple intraflagellar transport (IFT) and transition zone genes. Recently a zebrafish alms1 mutant was generated. The ALMS1 gene is the gene mutated in the ciliopathy Alström Syndrome a disease that causes hearing loss among other symptoms. The hearing loss seen in Alström Syndrome may be due in part to hair cell defects as...
• TMEM218 dysfunction causes ciliopathies, including Joubert and Meckel syndromes
  The Joubert-Meckel syndrome spectrum is a continuum of recessive ciliopathy conditions caused by primary cilium dysfunction. The primary cilium is a microtubule-based, antenna-like organelle that projects from the surface of most human cell types, allowing them to respond to extracellular signals. The cilium is partitioned from the cell body by the transition zone, a known hotspot for ciliopathy-related proteins. Despite years of Joubert syndrome (JBTS) gene discovery, the genetic cause cannot...
• Gene therapy reforms photoreceptor structure and restores vision in NPHP5-associated Leber congenital amaurosis
  The inherited childhood blindness caused by mutations in NPHP5, a form of Leber congenital amaurosis, results in abnormal development, dysfunction, and degeneration of photoreceptors. A naturally occurring NPHP5 mutation in dogs leads to a phenotype that very nearly duplicates the human retinopathy in terms of the photoreceptors involved, spatial distribution of degeneration, and the natural history of vision loss. We show that adeno-associated virus (AAV)-mediated NPHP5 gene augmentation of...
• COVID-PCD: a participatory research study on the impact of COVID-19 in people with primary ciliary dyskinesia
  COVID-PCD is a participatory study initiated by people with primary ciliary dyskinesia (PCD) who have an essential vote in all stages of the research from the design of the study to the recruitment of participants, and interpretation and communication of the study results. COVID-PCD aims to collect epidemiological data in real-time from people with PCD throughout the pandemic to describe incidence of coronavirus disease 2019 (COVID-19), symptoms and course of disease; identify risk factors for...
• The Prenatal Origins of Human Brain Asymmetry: Lessons Learned from a Cohort of Fetuses with Body Lateralization Defects
  Knowledge about structural brain asymmetries of human fetuses with body lateralization defects-congenital diseases in which visceral organs are partially or completely incorrectly positioned-can improve our understanding of the developmental origins of hemispheric brain asymmetry. This study investigated structural brain asymmetry in 21 fetuses, which were diagnosed with different types of lateralization defects; 5 fetuses with ciliopathies and 26 age-matched healthy control cases, between 22...