IFT Trains in Different Stages of Assembly Queue at the Ciliary Base
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PLATFORM ABSTRACTS Abstract Abstract Numbers Numbers Tuesday, November 6 41
American Society of Human Genetics 62nd Annual Meeting November 6–10, 2012 San Francisco, California PLATFORM ABSTRACTS Abstract Abstract Numbers Numbers Tuesday, November 6 41. Genes Underlying Neurological Disease Room 134 #196–#204 2. 4:30–6:30pm: Plenary Abstract 42. Cancer Genetics III: Common Presentations Hall D #1–#6 Variants Ballroom 104 #205–#213 43. Genetics of Craniofacial and Wednesday, November 7 Musculoskeletal Disorders Room 124 #214–#222 10:30am–12:45 pm: Concurrent Platform Session A (11–19): 44. Tools for Phenotype Analysis Room 132 #223–#231 11. Genetics of Autism Spectrum 45. Therapy of Genetic Disorders Room 130 #232–#240 Disorders Hall D #7–#15 46. Pharmacogenetics: From Discovery 12. New Methods for Big Data Ballroom 103 #16–#24 to Implementation Room 123 #241–#249 13. Cancer Genetics I: Rare Variants Room 135 #25–#33 14. Quantitation and Measurement of Friday, November 9 Regulatory Oversight by the Cell Room 134 #34–#42 8:00am–10:15am: Concurrent Platform Session D (47–55): 15. New Loci for Obesity, Diabetes, and 47. Structural and Regulatory Genomic Related Traits Ballroom 104 #43–#51 Variation Hall D #250–#258 16. Neuromuscular Disease and 48. Neuropsychiatric Disorders Ballroom 103 #259–#267 Deafness Room 124 #52–#60 49. Common Variants, Rare Variants, 17. Chromosomes and Disease Room 132 #61–#69 and Everything in-Between Room 135 #268–#276 18. Prenatal and Perinatal Genetics Room 130 #70–#78 50. Population Genetics Genome-Wide Room 134 #277–#285 19. Vascular and Congenital Heart 51. Endless Forms Most Beautiful: Disease Room 123 #79–#87 Variant Discovery in Genomic Data Ballroom 104 #286–#294 52. -
Synergistic Genetic Interactions Between Pkhd1 and Pkd1 Result in an ARPKD-Like Phenotype in Murine Models
BASIC RESEARCH www.jasn.org Synergistic Genetic Interactions between Pkhd1 and Pkd1 Result in an ARPKD-Like Phenotype in Murine Models Rory J. Olson,1 Katharina Hopp ,2 Harrison Wells,3 Jessica M. Smith,3 Jessica Furtado,1,4 Megan M. Constans,3 Diana L. Escobar,3 Aron M. Geurts,5 Vicente E. Torres,3 and Peter C. Harris 1,3 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background Autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct, with ADPKD usually caused by the genes PKD1 or PKD2 (encoding polycystin-1 and polycystin-2, respectively) and ARPKD caused by PKHD1 (encoding fibrocys- tin/polyductin [FPC]). Primary cilia have been considered central to PKD pathogenesis due to protein localization and common cystic phenotypes in syndromic ciliopathies, but their relevance is questioned in the simple PKDs. ARPKD’s mild phenotype in murine models versus in humans has hampered investi- gating its pathogenesis. Methods To study the interaction between Pkhd1 and Pkd1, including dosage effects on the phenotype, we generated digenic mouse and rat models and characterized and compared digenic, monogenic, and wild-type phenotypes. Results The genetic interaction was synergistic in both species, with digenic animals exhibiting pheno- types of rapidly progressive PKD and early lethality resembling classic ARPKD. Genetic interaction be- tween Pkhd1 and Pkd1 depended on dosage in the digenic murine models, with no significant enhancement of the monogenic phenotype until a threshold of reduced expression at the second locus was breached. -
Environmental Influences on Endothelial Gene Expression
ENDOTHELIAL CELL GENE EXPRESSION John Matthew Jeff Herbert Supervisors: Prof. Roy Bicknell and Dr. Victoria Heath PhD thesis University of Birmingham August 2012 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Tumour angiogenesis is a vital process in the pathology of tumour development and metastasis. Targeting markers of tumour endothelium provide a means of targeted destruction of a tumours oxygen and nutrient supply via destruction of tumour vasculature, which in turn ultimately leads to beneficial consequences to patients. Although current anti -angiogenic and vascular targeting strategies help patients, more potently in combination with chemo therapy, there is still a need for more tumour endothelial marker discoveries as current treatments have cardiovascular and other side effects. For the first time, the analyses of in-vivo biotinylation of an embryonic system is performed to obtain putative vascular targets. Also for the first time, deep sequencing is applied to freshly isolated tumour and normal endothelial cells from lung, colon and bladder tissues for the identification of pan-vascular-targets. Integration of the proteomic, deep sequencing, public cDNA libraries and microarrays, delivers 5,892 putative vascular targets to the science community. -
Evaluation of Variability in Human Kidney Organoids
ARTICLES https://doi.org/10.1038/s41592-018-0253-2 Evaluation of variability in human kidney organoids Belinda Phipson 1, Pei X. Er1, Alexander N. Combes1,2, Thomas A. Forbes1,3,4, Sara E. Howden1,2, Luke Zappia1,5, Hsan-Jan Yen1, Kynan T. Lawlor1, Lorna J. Hale1,4, Jane Sun6, Ernst Wolvetang6, Minoru Takasato1,7, Alicia Oshlack1,5 and Melissa H. Little 1,2,4* The utility of human pluripotent stem cell–derived kidney organoids relies implicitly on the robustness and transferability of the protocol. Here we analyze the sources of transcriptional variation in a specific kidney organoid protocol. Although individ- ual organoids within a differentiation batch showed strong transcriptional correlation, we noted significant variation between experimental batches, particularly in genes associated with temporal maturation. Single-cell profiling revealed shifts in neph- ron patterning and proportions of component cells. Distinct induced pluripotent stem cell clones showed congruent transcrip- tional programs, with interexperimental and interclonal variation also strongly associated with nephron patterning. Epithelial cells isolated from organoids aligned with total organoids at the same day of differentiation, again implicating relative matura- tion as a confounder. This understanding of experimental variation facilitated an optimized analysis of organoid-based disease modeling, thereby increasing the utility of kidney organoids for personalized medicine and functional genomics. he ability to derive induced pluripotent stem cells (iPSCs) In this study, we provide a comprehensive transcriptional from the somatic cells of patients1, together with directed dif- and morphological evaluation of our kidney organoid protocol. Tferentiation protocols, provides a capacity to model the cell Applying RNA sequencing (RNA-seq) to 57 whole organoids and types affected by disease. -
Cellular Ciliary Phenotyping Indicates Pathogenicity of Novel Variants in IFT140 and Confrms a Mainzer–Saldino Syndrome Diagnosis Machteld M
Oud et al. Cilia (2018) 7:1 https://doi.org/10.1186/s13630-018-0055-2 Cilia SHORT REPORT Open Access Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confrms a Mainzer–Saldino syndrome diagnosis Machteld M. Oud1,2* , Brooke L. Latour1,2‡, Zeineb Bakey1,2‡, Stef J. Letteboer1,2, Dorien Lugtenberg1, Ka Man Wu1,2, Elisabeth A. M. Cornelissen3, Helger G. Yntema1,4, Miriam Schmidts1,2,5, Ronald Roepman1,2† and Ernie M. H. F. Bongers1† Abstract Background: Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hear- ing difculties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. Methods: We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine- derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived Ift140 knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intrafa- gellar transport (IFT) were evaluated by immunocytochemistry. Results: Diagnostic WES revealed two novel compound heterozygous variants in IFT140, encoding IFT140. -
Blueprint Genetics Short Rib Dysplasia / Asphyxiating Thoracic Dysplasia Panel
Short Rib Dysplasia / Asphyxiating Thoracic Dysplasia Panel Test code: MA1101 Is a 18 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of asphyxiating thoracic dystrophy or short-rib dysplasia with or without polydactyly. The genes on this panel are included in the Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel. About Short Rib Dysplasia / Asphyxiating Thoracic Dysplasia Short-rib dysplasia (SRD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a trident aspect of the acetabular roof. SRD encompasses Ellis-van Creveld syndrome (EVC), Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib- polydactyly syndromes (SRPS, Beemer-Langer type, Majewski type, Saldino-Noonan type, Verma-Naumoff type), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Availability 4 weeks Gene Set Description Genes in the Short Rib Dysplasia / Asphyxiating Thoracic Dysplasia Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD CSPP1 Jeune asphyxiating thoracic dystrophy, Joubert -
High Diagnostic Yield in Skeletal Ciliopathies Using Massively Parallel Genome Sequencing, Structural Variant Screening and RNA Analyses
Journal of Human Genetics (2021) 66:995–1008 https://doi.org/10.1038/s10038-021-00925-x ARTICLE High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses 1 1 2,3 4 1 Anna Hammarsjö ● Maria Pettersson ● David Chitayat ● Atsuhiko Handa ● Britt-Marie Anderlid ● 5 6 7 8 9 Marco Bartocci ● Donald Basel ● Dominyka Batkovskyte ● Ana Beleza-Meireles ● Peter Conner ● 10 11 12,13 7,14 15 Jesper Eisfeldt ● Katta M. Girisha ● Brian Hon-Yin Chung ● Eva Horemuzova ● Hironobu Hyodo ● 16 1 17 18,19 20 Liene Korņejeva ● Kristina Lagerstedt-Robinson ● Angela E. Lin ● Måns Magnusson ● Shahida Moosa ● 11 10 21 15 18,22 Shalini S. Nayak ● Daniel Nilsson ● Hirofumi Ohashi ● Naoko Ohashi-Fukuda ● Henrik Stranneheim ● 1 23 24 19,22 1 7,25 Fulya Taylan ● Rasa Traberg ● Ulrika Voss ● Valtteri Wirta ● Ann Nordgren ● Gen Nishimura ● 1 1 Anna Lindstrand ● Giedre Grigelioniene Received: 4 December 2020 / Revised: 31 March 2021 / Accepted: 31 March 2021 / Published online: 20 April 2021 © The Author(s) 2021. This article is published with open access Abstract Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including 1234567890();,: 1234567890();,: 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 sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. -
Gene Ontology Functional Annotations and Pleiotropy
Network based analysis of genetic disease associations Sarah Gilman Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2013 Sarah Gilman All Rights Reserved ABSTRACT Network based analysis of genetic disease associations Sarah Gilman Despite extensive efforts and many promising early findings, genome-wide association studies have explained only a small fraction of the genetic factors contributing to common human diseases. There are many theories about where this “missing heritability” might lie, but increasingly the prevailing view is that common variants, the target of GWAS, are not solely responsible for susceptibility to common diseases and a substantial portion of human disease risk will be found among rare variants. Relatively new, such variants have not been subject to purifying selection, and therefore may be particularly pertinent for neuropsychiatric disorders and other diseases with greatly reduced fecundity. Recently, several researchers have made great progress towards uncovering the genetics behind autism and schizophrenia. By sequencing families, they have found hundreds of de novo variants occurring only in affected individuals, both large structural copy number variants and single nucleotide variants. Despite studying large cohorts there has been little recurrence among the genes implicated suggesting that many hundreds of genes may underlie these complex phenotypes. The question -
Partial Uniparental Isodisomy of Chromosome 16 Unmasks a Deleterious Biallelic Mutation in IFT140 That Causes Mainzer-Saldino Syndrome Benjamin M
Helm et al. Human Genomics (2017) 11:16 DOI 10.1186/s40246-017-0111-9 PRIMARY RESEARCH Open Access Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndrome Benjamin M. Helm1,2, Jason R. Willer3, Azita Sadeghpour3, Christelle Golzio3,4, Eric Crouch5, Samantha Schrier Vergano1,6, Nicholas Katsanis3* and Erica E. Davis3* Abstract 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. Results: Although clinical panel sequencing of genes implicated in nephrotic syndromes yielded no likely causal mutation, an oligo-SNP microarray identified a ~20-Mb region of homozygosity, with no altered gene dosage, on chromosome 16p13. Intersection of the proband’s phenotypes with known disease genes within the homozygous region yielded a single candidate, IFT140, encoding a retrograde intraflagellar transport protein implicated previously in several ciliopathies, including the phenotypically overlapping Mainzer-Saldino syndrome (MZSDS). Sanger sequencing yielded a maternally inherited homozygous c.634G>A; p.Gly212Arg mutation altering the exon 6 splice donor site. Functional studies in cells from the proband showed that the locus produced two transcripts: a majority message containing a mis-splicing event that caused a premature termination codon and a minority message homozygous for the p.Gly212Arg allele. -
Integrative Clinical Sequencing in the Management of Refractory Or
Supplementary Online Content Mody RJ, Wu Y-M, Lonigro RJ, et al. Integrative Clinical Sequencing in the Management of Children and Young Adults With Refractory or Relapsed CancerJAMA. doi:10.1001/jama.2015.10080. eAppendix. Supplementary appendix This supplementary material has been provided by the authors to give readers additional information about their work. © 2015 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 SUPPLEMENTARY APPENDIX Use of Integrative Clinical Sequencing in the Management of Pediatric Cancer Patients *#Rajen J. Mody, M.B.B.S, M.S., *Yi-Mi Wu, Ph.D., Robert J. Lonigro, M.S., Xuhong Cao, M.S., Sameek Roychowdhury, M.D., Ph.D., Pankaj Vats, M.S., Kevin M. Frank, M.S., John R. Prensner, M.D., Ph.D., Irfan Asangani, Ph.D., Nallasivam Palanisamy Ph.D. , Raja M. Rabah, M.D., Jonathan R. Dillman, M.D., Laxmi Priya Kunju, M.D., Jessica Everett, M.S., Victoria M. Raymond, M.S., Yu Ning, M.S., Fengyun Su, Ph.D., Rui Wang, M.S., Elena M. Stoffel, M.D., Jeffrey W. Innis, M.D., Ph.D., J. Scott Roberts, Ph.D., Patricia L. Robertson, M.D., Gregory Yanik, M.D., Aghiad Chamdin, M.D., James A. Connelly, M.D., Sung Choi, M.D., Andrew C. Harris, M.D., Carrie Kitko, M.D., Rama Jasty Rao, M.D., John E. Levine, M.D., Valerie P. Castle, M.D., Raymond J. Hutchinson, M.D., Moshe Talpaz, M.D., ^Dan R. Robinson, Ph.D., and ^#Arul M. Chinnaiyan, M.D., Ph.D. CORRESPONDING AUTHOR (S): # Arul M. -
Mendelian Pathway Analysis of Laboratory Traits Reveals Distinct Roles for Ciliary Subcompartments in Common Disease Pathogenesis
bioRxiv preprint doi: https://doi.org/10.1101/2020.08.31.275685; this version posted September 2, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Mendelian pathway analysis of laboratory traits reveals distinct roles for ciliary subcompartments in common disease pathogenesis Theodore George Drivas1,2, Anastasia Lucas1, Xinyuan Zhang1, Marylyn DeRiggi Ritchie1 1 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19194, USA 2 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA Summary: Rare monogenic disorders of the primary cilium, termed ciliopathies, are characterized By extreme presentations of otherwise-common diseases, such as diaBetes, hepatic fiBrosis, and kidney failure. However, despite a revolution in our understanding of the cilium’s role in rare disease pathogenesis, the organelle’s contriBution to common disease remains largely unknown. We hypothesized that common genetic variants affecting Mendelian ciliopathy genes might also contriBute to common complex diseases pathogenesis more generally. To address this question, we performed association studies of 16,875 common genetic variants across 122 well- characterized ciliary genes with 12 quantitative laBoratory traits characteristic of ciliopathy syndromes in 378,213 European-ancestry individuals in the UK BioBank. We incorporated tissue- specific gene expression analysis, expression quantitative trait loci (eQTL) and Mendelian disease information into our analysis, and replicated findings in meta-analysis to increase our confidence in oBserved associations Between ciliary genes and human phenotypes. -
HSP90-Incorporating Chaperome Networks As Biosensor for Disease-Related Pathways in Patient- Specific Midbrain Dopamine Neurons
ARTICLE DOI: 10.1038/s41467-018-06486-6 OPEN HSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient- specific midbrain dopamine neurons Sarah Kishinevsky1,2,3,4, Tai Wang3, Anna Rodina3, Sun Young Chung1,2, Chao Xu3, John Philip5, Tony Taldone3, Suhasini Joshi3, Mary L. Alpaugh3,14, Alexander Bolaender3, Simon Gutbier6, Davinder Sandhu7, Faranak Fattahi1,2, Bastian Zimmer1,2, Smit K. Shah3, Elizabeth Chang5, Carmen Inda3,15, John Koren 3rd3,16, Nathalie G. Saurat1,2, Marcel Leist 6, Steven S. Gross7, Venkatraman E. Seshan8, Christine Klein9, Mark J. Tomishima1,2,10, Hediye Erdjument-Bromage11,12, Thomas A. Neubert 11,12, Ronald C. Henrickson5, 1234567890():,; Gabriela Chiosis3,13 & Lorenz Studer1,2 Environmental and genetic risk factors contribute to Parkinson’s Disease (PD) pathogenesis and the associated midbrain dopamine (mDA) neuron loss. Here, we identify early PD pathogenic events by developing methodology that utilizes recent innovations in human pluripotent stem cells (hPSC) and chemical sensors of HSP90-incorporating chaperome networks. We show that events triggered by PD-related genetic or toxic stimuli alter the neuronal proteome, thereby altering the stress-specific chaperome networks, which produce changes detected by chemical sensors. Through this method we identify STAT3 and NF-κB signaling activation as examples of genetic stress, and phospho-tyrosine hydroxylase (TH) activation as an example of toxic stress-induced pathways in PD neurons. Importantly, pharmacological inhibition of the stress chaperome network reversed abnormal phospho- STAT3 signaling and phospho-TH-related dopamine levels and rescued PD neuron viability. The use of chemical sensors of chaperome networks on hPSC-derived lineages may present a general strategy to identify molecular events associated with neurodegenerative diseases.