CT and MR Imaging Findings in the Joubert Syndrome,a“Ciliopathy”

A 7-year-old boy presented with cerebellar ataxia with reduced tonicity, deficits of the fine and gross motor coordination skills and vestibular stimulus processing, as well as significantly delayed language development. MR imaging showed the so-called “molar tooth sign”, which was highly pathognomonic for the Joubert-Syndrome—an inherited cerebellar ataxia with a variety of clinical symptoms—and related entities. It is caused by a complex malformation of the cerebellar vermis and the midbrain. The cerebellar vermis is hypoplastic or completely absent;at the same time, the superior cerebellar peduncles are thickened. There is a lack of normal decussation of the fiber tracts in mesencephalon, which follow an abnormal horizontal course, as well as a lack of the decussation of the corticospinal fiber tracts in the caudal medulla oblongata and deformity of the 4th ventricle. Clinically, the triad of cerebellar ataxia, developmental retardation, and abnormal eye movements is indicating a related syndrome of this spectrum. The appearance of the involved children is characterized by dysmorphic facial features with epicanthus, broad nose bridge, low set ears and typically triangularly shaped and opened mouth. The diagnosis is usually made by imaging and clinical findings. Recently, advantages were made in genetic research on the Joubert syndrome and interesting findings published about diffusion tensor imaging and tractography. However, standard MR imaging, applying an adequate imaging protocol including sequences with excellent T1 contrast and 3D imaging with isotropic spatial resolution allowing reconstructions in all orientations, remains an essential tool for making this diagnosis.

Characterization of two novel knock-in mouse models of syndromic retinal ciliopathy carrying hypomorphic Sdccag8 mutations

Mutations in serologically defined colon cancer autoantigen protein 8(SDCCAG8)were first identified in retinal ciliopathy families a decade ago with unknown function.To investigate the pathogenesis of SDCCAG8-associated retinal ciliopathies in vivo,we employed CRISPR/Cas9-mediated homology-directed recombination(HDR)to generate two knock-in mouse models,Sdccag8^(Y236X/Y236X) and Sdccag8^(E451GfsX467/E451GfsX467),which carry truncating mutations of the mouse Sdccag8,corresponding to mutations that cause Bardet-Biedl syndrome(BBS)and Senior-L?ken syndrome(SLS)(c.696T>G p.Y232X and c.1339-1340ins G p.E447GfsX463)in humans,respectively.The two mutant Sdccag8 knock-in mice faithfully recapitulated human SDCCAG8-associated BBS phenotypes such as rod-cone dystrophy,cystic renal disorder,polydactyly,infertility,and growth retardation,with varied age of onset and severity depending on the hypomorphic strength of the Sdccag8 mutations.To the best of our knowledge,these knock-in mouse lines are the first BBS mouse models to present with the polydactyly phenotype.Major phototransduction protein mislocalization was also observed outside the outer segment after initiation of photoreceptor degeneration.Impaired cilia were observed in the mutant photoreceptors,renal epithelial cells,and mouse embryonic fibroblasts derived from the knock-in mouse embryos,suggesting that SDCCAG8 plays an essential role in ciliogenesis,and cilium defects are a primary driving force of SDCCAG8-associated retinal ciliopathies.

Phenotypical Aspects of a Familial Syndromic Retinitis Pigmentosa

Aim: To report a familial case of syndromic retinitis pigmentosa identified at Aristide Le Dantec Hospital in Dakar and to describe their clinical characteristics ophthalmic. Observation: We report a sibling group of nine children, four died at a young age from unknown causes. Three children were affected by retinitis pigmentosa, two cases were syndromic. A history of nyctalopia was found in all three affected children. The mean age of onset of decreased visual acuity was 6.6 years. Patient 1 affected by syndromic retinitis pigmentosa had an extraocular sign of cystic dilation of the main bile duct. Patient 2 had myoclonic epilepsy, psychomotor retardation, and the molar tooth sign on cerebral MRI (highly suggestive of Joubert syndrome). The third child had isolated retinitis pigmentosa. Ophthalmological examinations (fundus examination, electroretinogram, and visual evoked potentials) and pediatric examinations in the remaining two children were normal. Discussion and Conclusion: Retinitis pigmentosa is a rare degenerative disease that can be associated with several other malformations, highlighting the importance of screening for associated conditions. It presents a grim functional prognosis and a life prognosis dependent on extraocular manifestations. Molecular biology (karyotyping, next-generation sequencing) could have identified the implicated genes and allowed for a formal diagnosis and genetic counseling.

Cell cycle regulation through primary cilium:A long-forgotten story

Protruded from cytomembrane,primary cilium is a widespread cell organelle that can be found in almost all cell types in Mammalia.Because of its comprehensive requirement in various cellular activities and various functions in different organs,primary cilium has been a valuable research area of human pathology research since the turn of the millennium.And the potential application of the interaction between primary cilia and cell cycle regulation may be the most promising direction as many primary cilium-caused diseases are found to be caused by cell cycle dysregulation resulted from primary cilia defects.Therefore,a deep understanding of the interaction between primary cilia and the cell cycle is in great need.Hence in this review,we mainly described how the interaction between primary cilia and cell cycle proceeds and demonstrated three hypotheses raised from much different research.These hypotheses include(1)Primary cilium as a cellular signaling hub to regulate the cell cycle,(2)Primary cilium as a reservoir of cell cycle regulation-related factors,and(3)Primary cilium as a cell cycle checkpoint or a brake.Nonetheless,we also call for more attention on research of interaction between cell cycle and primary cilia and tried to point out some possible research directions for those who are interested.

Potential Application of TCM Sophoridine in Regulating Intensity of Autophagy to Treat PKD

Nearly all cells have primary cilia( PC) composed of microtubules,primary cilia mainly functioning as sensing various signals of the environment and coordinating intracellular signaling pathways. Autophagy is an adaptive response of cells to environmental stress such as starvation/inflammation and infection. Many ciliopathies may induce autophagy. Polycystic kidney disease( PKD) is the most common ciliopathy,with the incidence of 1/500 to 1/1 000 in the world. A typical symptom of the PKD is the chronic development of multiple renal cysts that may eventually develop into advanced kidney disease. Sophoridine is an alkaloid extracted from the traditional Chinese medicinal plant Sophora alopecuroides L. It is a new antitumor drug which has the function of inducing cell autophagy. This paper mainly discussed the possibility of treating PKD through sophoridine inducing autophagy.

Peripheral and central control of obesity by primary cilia

Primary cilia are hair-like structures that protrude from the cell surface.They are capable of sensing external cues and conveying a vast array of signals into cells to regulate a variety of physiological activities.Mutations in cilium-associated genes are linked to a group of diseases with overlapping clinical manifestations,collectively known as ciliopathies.A significant proportion of human ciliopathy cases are accompanied by metabolic disorders such as obesity and type 2 diabetes.Nevertheless,the mechanisms through which dysfunction of primary cilia contributes to obesity are complex.In this review,we present an overview of primary cilia and highlight obesity-related ciliopathies.We also discuss the potential role of primary cilia in peripheral organs,with a focus on adipose tissues.In addition,we emphasize the significance of primary cilia in the central regulation of obesity,especially the involvement of ciliary signaling in the hypothalamic control of feeding behavior.This review therefore proposes a framework of both peripheral and central regulation of obesity by primary cilia,which may benefit further exploration of the ciliary role in metabolic regulation.

The actin-bundling protein Fascin-1 modulates ciliary signalling

Primary cilia are microtubule-based cell organelles important for cellular communication. Since they are involved in the regulation of numerous signalling pathways, defects in cilia development or function are associated with genetic disorders, collectively called ciliopathies. Besides their ciliary functions, recent research has shown that several ciliary proteins are involved in the coordination of the actin cytoskeleton. Although ciliary and actin phenotypes are related, the exact nature of their interconnection remains incompletely understood. Here, we show that the protein BBS6, associated with the ciliopathy Bardet–Biedl syndrome, cooperates with the actin-bundling protein Fascin-1 in regulating filopodia and ciliary signalling. We found that loss of Bbs6 affects filopodia length potentially via attenuated interaction with Fascin-1. Conversely, loss of Fascin-1 leads to a ciliary phenotype, subsequently affecting ciliary Wnt signalling, possibly in collaboration with BBS6. Our data shed light on how ciliary proteins are involved in actin regulations and provide new insight into the involvement of the actin regulator Fascin-1 in ciliogenesis and cilia-associated signalling. Advancing our knowledge of the complex regulations between primary cilia and actin dynamics is important to understand the pathogenic consequences of ciliopathies.

New insights into the roles for DYRK family in mammalian development and congenital diseases

The dual-specificity tyrosine-regulated kinase (DYRK) family is evolutionarily conserved from invertebrate to mammals. DYRKs regulate cell proliferation, apoptosis, survival, and differentiation by modifying the protein activation state, cellular localization, and turnover. In contrast to several studies in cellular models, the available evidence regarding the in vivo roles of DYRKs in mammalian development is limited. This review summarizes the in vivo studies on Dyrks which provide insight into their roles in mammalian tissue development and congenital diseases. In vivo evidence obtained using knockout and genetically modified animals helps to understand and develop novel clinical therapies and drug for human congenital diseases, such as Down syndrome and neuronal disorders (associated with DYRK1A) and skeletal ciliopathies (associated with DYRK2).

Zebrafish as a Model for Human Ciliopathies

Cilia, microtubule-based structures found on the surface of almost all vertebrate cells, play an array of diverse biological functions. Abnormal ciliary axonemal structure and function can result in a class of genetic disorders that are collectively termed ciliopathies. Model organisms, including Chlamydomonas reinhardtii and Caenorhabditis elegans have been widely used to study the complex genetic basis of ciliopathies. Here, we review the advantages of the zebrafish as a vertebrate model for human ciliopathies. We summarize the features of zebrafish cilia, and the major findings and contributions of the zebrafish model in recent studies of human ciliopathies. We also discuss the new genome editing approaches being efficiently used in zebrafish, and the exciting prospects of these approaches in modeling human ciliopathies.

Cilia and ciliopathies:From Chlamydomonas and beyond

The biological function of motile cilia/flagella has long been recognized. The non-motile primary cilium, once regarded as a vestigial organelle, however, has been found recently to play unexpected roles in mammalian physiology and development. Defects in cilia have profound impact on human health. Diseases related to cilia, collectively called ciliopathies include male infertility, primary cilia dyskinesia, renal cyst formation, blindness, polydactyly, obesity, hypertension, and even mental retardation. Our current understanding of cilia and ciliopathies has been fueled by basic research employing various model organisms including Chlamydomonas, a unicellular green alga. This review article provides a general introduction to the cell biology of cilia and an overview of various cilia-related diseases.

Small GTPases and cilia

Small GTPases are key molecular switches that bind and hydrolyze GTP in diverse membrane-and cytoskeletonrelated cellular processes.Recently,mounting evidences have highlighted the role of various small GTPases,including the members in Arf/Arl,Rab,and Ran subfamilies,in cilia formation and function.Once overlooked as an evolutionary vestige,the primary cilium has attracted more and more attention in last decade because of its role in sensing various extracellular signals and the association between cilia dysfunction and a wide spectrum of human diseases,now called ciliopathies.Here we review recent advances about the function of small GTPases in the context of cilia,and the correlation between the functional impairment of small GTPases and ciliopathies.Understanding of these cellular processes is of fundamental importance for broadening our view of cilia development and function in normal and pathological states and for providing valuable insights into the role of various small GTPases in disease processes,and their potential as therapeutic targets.

Multifaceted roles of centrosomes in development,health,and disease

The centrosome is a membrane-less organelle consisting of a pair of barrel-shaped centrioles and pericentriolar material and functions as the major microtubule-organizing center and signaling hub in animal cells.The past decades have witnessed the functional complexity and importance of centrosomes in various cellular processes such as cell shaping,division,and migration.In addition,centrosome abnormalities are linked to a wide range of human diseases and pathological states,such as cancer,reproductive disorder,brain disease,and ciliopathies.Herein,we discuss various functions of centrosomes in development and health,with an emphasis on their roles in germ cells,stem cells,and immune responses.We also discuss how centrosome dysfunctions are involved in diseases.A better understanding of the mechanisms regulating centrosome functions may lead the way to potential therapeutic targeting of this organelle in disease treatment.

Cilia in cell signaling and human disorders

One of the most widespread cellular organelles in nature is cilium,which is found in many unicellular and multicellular organisms.Formerly thought to be a mostly vestigial organelle,the cilium has been discovered in the past several decades to play critical motile and sensory roles involved in normal organogenesis during development.The role of cilia has also been implicated in an ever increasing array of seemingly unrelated human diseases,including blindness,kidney cysts,neural tube defects and obesity.In this article we review some of the recent developments in research on cilia,and how defects in ciliogenesis and function can give rise to developmental disorders and disease.