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Ciliopathy

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https://www.readbyqxmd.com/read/28800606/whole-exome-sequencing-as-a-diagnostic-tool-for-patients-with-ciliopathy-like-phenotypes
#1
Sheila Castro-Sánchez, María Álvarez-Satta, Mohamed A Tohamy, Sergi Beltran, Sophia Derdak, Diana Valverde
Ciliopathies are a group of rare disorders characterized by a high genetic and phenotypic variability, which complicates their molecular diagnosis. Hence the need to use the latest powerful approaches to faster identify the genetic defect in these patients. We applied whole exome sequencing to six consanguineous families clinically diagnosed with ciliopathy-like disease, and for which mutations in predominant Bardet-Biedl syndrome (BBS) genes had previously been excluded. Our strategy, based on first applying several filters to ciliary variants and using many of the bioinformatics tools available, allowed us to identify causal mutations in BBS2, ALMS1 and CRB1 genes in four families, thus confirming the molecular diagnosis of ciliopathy...
2017: PloS One
https://www.readbyqxmd.com/read/28771248/interpreting-the-clinical-significance-of-combined-variants-in-multiple-recessive-disease-genes-systematic-investigation-of-joubert-syndrome-yields-little-support-for-oligogenicity
#2
Ian G Phelps, Jennifer C Dempsey, Megan E Grout, Christine R Isabella, Hannah M Tully, Dan Doherty, Ruxandra Bachmann-Gagescu
PurposeNext-generation sequencing (NGS) often identifies multiple rare predicted-deleterious variants (RDVs) in different genes associated with a recessive disorder in a given patient. Such variants have been proposed to contribute to digenicity/oligogenicity or "triallelism" or to act as genetic modifiers.MethodsUsing the recessive ciliopathy Joubert syndrome (JBTS) as a model, we investigated these possibilities systematically, relying on NGS of known JBTS genes in a large JBTS and two control cohorts.Results65% of affected individuals had a recessive genetic cause, while 4...
August 3, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/28726664/expanded-phenotype-of-tmem67-gene-mutation-case-report
#3
T Tkemaladze, G Melikishvili, V Kherkheulidze, A Melikishvili, T Davitaia
Human ciliopathies are a class of multi-organ genetic disorders caused by defects of proteins expressed at the primary cilium, an organelle present on the cell surface of almost all cell types. Thus far, dozens of causative genes for ciliopathies have been identified and many of them are known to cause allelic disease. Of particular interest is the TMEM67 gene, encoding the transmembrane protein meckelin. The involvement of the mutant TMEM67 gene is known to be associated with a broad range of clinical presentations, namely Joubert syndrome 6 (JBTS6), nephronophthisis 11 (NPHP11), Bardet-Biedel syndrome (BBS), COACH syndrome, and lethal Meckel syndrome type 3 (MKS3)...
June 2017: Georgian Medical News
https://www.readbyqxmd.com/read/28724397/partial-uniparental-isodisomy-of-chromosome-16-unmasks-a-deleterious-biallelic-mutation-in-ift140-that-causes-mainzer-saldino-syndrome
#4
Benjamin M Helm, Jason R Willer, Azita Sadeghpour, Christelle Golzio, Eric Crouch, Samantha Schrier Vergano, Nicholas Katsanis, Erica E Davis
BACKGROUND: The ciliopathies represent an umbrella group of >50 clinical entities that share both clinical features and molecular etiology underscored by structural and functional defects of the primary cilium. Despite the advances in gene discovery, this group of entities continues to pose a diagnostic challenge, in part due to significant genetic and phenotypic heterogeneity and variability. We consulted a pediatric case from asymptomatic, non-consanguineous parents who presented as a suspected ciliopathy due to a constellation of retinal, renal, and skeletal findings...
July 19, 2017: Human Genomics
https://www.readbyqxmd.com/read/28717663/refining-genotype-phenotype-correlation-in-alstr%C3%A3-m-syndrome-through-study-of-primary-human-fibroblasts
#5
Jian-Hua Chen, Tarekegn Geberhiwot, Timothy G Barrett, Richard Paisey, Robert K Semple
BACKGROUND: Alström syndrome (AS), featuring retinal dystrophy, neuronal deafness, cardiomyopathy, metabolic syndrome, and diffuse fibrosis, is caused by biallelic mutations in the centrosomal protein ALMS1. Genotype-phenotype correlation has been suggested without assessment of ALMS1 expression. METHODS: ALMS1 expression (real-time PCR and immunocytochemistry) and cilia formation (immunocytochemistry) were assessed in fibroblasts from deeply phenotyped volunteers diagnosed with AS recruited from a dedicated AS Service...
July 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/28710492/nek1-kinase-domain-structure-and-its-dynamic-protein-interactome-after-exposure-to-cisplatin
#6
Talita D Melo-Hanchuk, Priscila Ferreira Slepicka, Gabriela Vaz Meirelles, Fernanda Luisa Basei, Diogo Ventura Lovato, Daniela Campos Granato, Bianca Alves Pauletti, Romenia Ramos Domingues, Adriana Franco Paes Leme, Alessandra Luiza Pelegrini, Guido Lenz, Stefan Knapp, Jonathan M Elkins, Jörg Kobarg
NEK family kinases are serine/threonine kinases that have been functionally implicated in the regulation of the disjunction of the centrosome, the assembly of the mitotic spindle, the function of the primary cilium and the DNA damage response. NEK1 shows pleiotropic functions and has been found to be mutated in cancer cells, ciliopathies such as the polycystic kidney disease, as well as in the genetic diseases short-rib thoracic dysplasia, Mohr-syndrome and amyotrophic lateral sclerosis. NEK1 is essential for the ionizing radiation DNA damage response and priming of the ATR kinase and of Rad54 through phosphorylation...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28710093/the-ciliary-membrane-associated-proteome-reveals-actin-binding-proteins-as-key-components-of-cilia
#7
Priyanka Kohli, Martin Höhne, Christian Jüngst, Sabine Bertsch, Lena K Ebert, Astrid C Schauss, Thomas Benzing, Markus M Rinschen, Bernhard Schermer
Primary cilia are sensory, antennae-like organelles present on the surface of many cell types. They have been involved in a variety of diseases collectively termed ciliopathies. As cilia are essential regulators of cell signaling, the composition of the ciliary membrane needs to be strictly regulated. To understand regulatory processes at the ciliary membrane, we report the targeting of a genetically engineered enzyme specifically to the ciliary membrane to allow biotinylation and identification of the membrane-associated proteome...
July 14, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28704921/eys-mutations-causing-autosomal-recessive-retinitis-pigmentosa-changes-of-retinal-structure-and-function-with-disease-progression
#8
David B McGuigan, Elise Heon, Artur V Cideciyan, Rinki Ratnapriya, Monica Lu, Alexander Sumaroka, Alejandro J Roman, Vaishnavi Batmanabane, Alexandra V Garafalo, Edwin M Stone, Anand Swaroop, Samuel G Jacobson
Mutations in the EYS (eyes shut homolog) gene are a common cause of autosomal recessive (ar) retinitis pigmentosa (RP). Without a mammalian model of human EYS disease, there is limited understanding of details of disease expression and rates of progression of the retinal degeneration. We studied clinically and with chromatic static perimetry, spectral-domain optical coherence tomography (OCT), and en face autofluoresence imaging, a cohort of 15 patients (ages 12-51 at first visit), some of whom had longitudinal data of function and structure...
July 12, 2017: Genes
https://www.readbyqxmd.com/read/28700940/in%C3%A2-vitro-modeling-using-ciliopathy-patient-derived-cells-reveals-distinct-cilia-dysfunctions-caused-by-cep290-mutations
#9
Hiroko Shimada, Quanlong Lu, Christine Insinna-Kettenhofen, Kunio Nagashima, Milton A English, Elizabeth M Semler, Jacklyn Mahgerefteh, Artur V Cideciyan, Tiansen Li, Brian P Brooks, Meral Gunay-Aygun, Samuel G Jacobson, Tiziana Cogliati, Christopher J Westlake, Anand Swaroop
Mutations in CEP290, a transition zone protein in primary cilia, cause diverse ciliopathies, including Leber congenital amaurosis (LCA) and Joubert-syndrome and related disorders (JSRD). We examined cilia biogenesis and function in cells derived from CEP290-LCA and CEP290-JSRD patients. CEP290 protein was reduced in LCA fibroblasts with no detectable impact on cilia; however, optic cups derived from induced pluripotent stem cells (iPSCs) of CEP290-LCA patients displayed less developed photoreceptor cilia. Lack of CEP290 in JSRD fibroblasts resulted in abnormal cilia and decreased ciliogenesis...
July 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28698599/genes-and-molecular-pathways-underpinning-ciliopathies
#10
REVIEW
Jeremy F Reiter, Michel R Leroux
Motile and non-motile (primary) cilia are nearly ubiquitous cellular organelles. The dysfunction of cilia causes diseases known as ciliopathies. The number of reported ciliopathies (currently 35) is increasing, as is the number of established (187) and candidate (241) ciliopathy-associated genes. The characterization of ciliopathy-associated proteins and phenotypes has improved our knowledge of ciliary functions. In particular, investigating ciliopathies has helped us to understand the molecular mechanisms by which the cilium-associated basal body functions in early ciliogenesis, as well as how the transition zone functions in ciliary gating, and how intraflagellar transport enables cargo trafficking and signalling...
July 12, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28690834/from-disease-modelling-to-personalised-therapy-in-patients-with-cep290-mutations
#11
Elisa Molinari, Shalabh Srivastava, John A Sayer, Simon A Ramsbottom
Mutations that give rise to premature termination codons are a common cause of inherited genetic diseases. When transcripts containing these changes are generated, they are usually rapidly removed by the cell through the process of nonsense-mediated decay. Here we discuss observed changes in transcripts of the centrosomal protein CEP290 resulting not from degradation, but from changes in exon usage. We also comment on a landmark paper (Drivas et al. Sci Transl Med. 2015) where modelling this process of exon usage may be used to predict disease severity in CEP290 ciliopathies, and how understanding this process may potentially be used for therapeutic benefit in the future...
2017: F1000Research
https://www.readbyqxmd.com/read/28687664/tubulin-glycylation-controls-primary-cilia-length
#12
Sudarshan Gadadhar, Hala Dadi, Satish Bodakuntla, Anne Schnitzler, Ivan Bièche, Filippo Rusconi, Carsten Janke
As essential components of the eukaryotic cytoskeleton, microtubules fulfill a variety of functions that can be temporally and spatially controlled by tubulin posttranslational modifications. Tubulin glycylation has so far been mostly found on motile cilia and flagella, where it is involved in the stabilization of the axoneme. In contrast, barely anything is known about the role of glycylation in primary cilia because of limitations in detecting this modification in these organelles. We thus developed novel glycylation-specific antibodies with which we detected glycylation in many primary cilia...
July 7, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28679688/compound-heterozygous-alterations-in-intraflagellar-transport-protein-cluap1-in-a-child-with-a-novel-joubert-and-oral-facial-digital-overlap-syndrome
#13
Jennifer J Johnston, Chanjae Lee, Ingrid M Wentzensen, Melissa A Parisi, Molly M Crenshaw, Julie C Sapp, Jeffrey M Gross, John B Wallingford, Leslie G Biesecker
Disruption of normal ciliary function results in a range of diseases collectively referred to as ciliopathies. Here we report a child with a phenotype that overlapped with Joubert, oral-facial-digital, and Pallister-Hall syndromes including brain, limb, and craniofacial anomalies. We performed exome-sequence analysis on a proband and both parents, filtered for putative causative variants, and Sanger-verified variants of interest. Identified variants in CLUAP1 were functionally analyzed in a Xenopus system to determine their effect on ciliary function...
July 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28675157/cytoplasmic-e2f4-forms-organizing-centres-for-initiation-of-centriole-amplification-during-multiciliogenesis
#14
Munemasa Mori, Renin Hazan, Paul S Danielian, John E Mahoney, Huijun Li, Jining Lu, Emily S Miller, Xueliang Zhu, Jacqueline A Lees, Wellington V Cardoso
Abnormal development of multiciliated cells is a hallmark of a variety of human conditions associated with chronic airway diseases, hydrocephalus and infertility. Multiciliogenesis requires both activation of a specialized transcriptional program and assembly of cytoplasmic structures for large-scale centriole amplification that generates basal bodies. It remains unclear, however, what mechanism initiates formation of these multiprotein complexes in epithelial progenitors. Here we show that this is triggered by nucleocytoplasmic translocation of the transcription factor E2f4...
July 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/28667057/an-elusive-ciliopathy-joubert-syndrome
#15
Carlo Canepa, Ben Burton, Abdul Muhith
The police brought a 65-year-old female patient to the EADU after being found 'roaming the streets' in an apparent state of confusion. This was her third admission under the same circumstances during the last 3 years. Neurological examination revealed (1) cognitive impairment, (2) oculomotor apraxia, (3) abnormal cancellation of vestibular ocular reflex, (4) mild ataxia and (5) mild hypotonia. Renal function was abnormal and liver function was normal. No retinal disturbance was found. The head CT on admission was normal for stroke and the lumbar puncture was negative for encephalitis...
June 29, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28662344/oral-and-craniofacial-anomalies-of-bardet-biedl-syndrome-dental-management-in-the-context-of-a-rare-disease
#16
A Panny, I Glurich, R M Haws, A Acharya
Standardized guidelines for the oral health management of patients with rare diseases exhibiting morphologic anomalies are currently lacking. This review considers Bardet-Biedl syndrome (BBS), a monogenic autosomal recessive nonmotile ciliopathy, as an archetypal condition. Dental anomalies are present in a majority of individuals affected by BBS due to abnormal embryonic orofacial and tooth development. Genetically encoded intrinsic oral structural anomalies and heterogeneous BBS clinical phenotypes and consequent oral comorbidities confound oral health management...
June 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28659385/cep19-cooperates-with-fop-and-cep350-to-drive-early-steps-in-the-ciliogenesis-programme
#17
Bahareh A Mojarad, Gagan D Gupta, Monica Hasegan, Oumou Goudiam, Renata Basto, Anne-Claude Gingras, Laurence Pelletier
Primary cilia are microtubule-based sensory organelles necessary for efficient transduction of extracellular cues. To initiate cilia formation, ciliary vesicles (CVs) are transported to the vicinity of the centrosome where they dock to the distal end of the mother centriole and fuse to initiate cilium assembly. However, to this date, the early steps in cilia formation remain incompletely understood. Here, we demonstrate functional interplay between CEP19, FOP and CEP350 in ciliogenesis. Using three-dimensional structured-illumination microscopy (3D-SIM) imaging, we mapped the relative spatial distribution of these proteins at the distal end of the mother centriole and show that CEP350/FOP act upstream of CEP19 in their recruitment hierarchy...
June 2017: Open Biology
https://www.readbyqxmd.com/read/28640449/polycystic-kidney-disease
#18
Joseph Ghata, Benjamin D Cowley
Renal cysts, which arise from renal tubules, can be seen in a variety of hereditary and nonhereditary entities. Common mechanisms associated with renal cyst formation include increased cell proliferation, epithelial fluid secretion, and extracellular matrix remodeling. Hereditary polycystic kidney disease (PKD) is seen as a component of numerous diseases. Autosomal dominant (AD) PKD is the most common potentially fatal hereditary disease in humans, causes renal failure in approximately 50% of affected individuals, and accounts for approximately 5% of end stage renal disease cases in the United States...
June 18, 2017: Comprehensive Physiology
https://www.readbyqxmd.com/read/28630322/tcte1-is-a-conserved-component-of-the-dynein-regulatory-complex-and-is-required-for-motility-and-metabolism-in-mouse-spermatozoa
#19
Julio M Castaneda, Rong Hua, Haruhiko Miyata, Asami Oji, Yueshuai Guo, Yiwei Cheng, Tao Zhou, Xuejiang Guo, Yiqiang Cui, Bin Shen, Zibin Wang, Zhibin Hu, Zuomin Zhou, Jiahao Sha, Renata Prunskaite-Hyyrylainen, Zhifeng Yu, Ramiro Ramirez-Solis, Masahito Ikawa, Martin M Matzuk, Mingxi Liu
Flagella and cilia are critical cellular organelles that provide a means for cells to sense and progress through their environment. The central component of flagella and cilia is the axoneme, which comprises the "9+2" microtubule arrangement, dynein arms, radial spokes, and the nexin-dynein regulatory complex (N-DRC). Failure to properly assemble components of the axoneme leads to defective flagella and in humans leads to a collection of diseases referred to as ciliopathies. Ciliopathies can manifest as severe syndromic diseases that affect lung and kidney function, central nervous system development, bone formation, visceral organ organization, and reproduction...
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28625917/the-cholangiocyte-primary-cilium-in-health-and-disease
#20
REVIEW
Adrian P Mansini, Estanislao Peixoto, Kristen M Thelen, Cesar Gaspari, Sujeong Jin, Sergio A Gradilone
Cholangiocytes, like most cells, express primary cilia extending from their membranes. These organelles function as antennae which detect stimuli from bile and transmit the information into cells regulating several signaling pathways involved in secretion, proliferation and apoptosis. The ability of primary cilia to detect different signals is provided by ciliary associated proteins which are expressed in its membrane. Defects in the structure and/or function of these organelles lead to cholangiociliopathies that result in cholangiocyte hyperproliferation, altered fluid secretion and absorption...
June 15, 2017: Biochimica et Biophysica Acta
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