DOCSLIB.ORG

Shimada 2017.Pdf

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Shimada 2017.Pdf Article In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations Graphical Abstract Authors Control CEP290-JSRD Hiroko Shimada, Quanlong Lu, Christine Insinna-Kettenhofen, ..., Cilium GPR161 Cilium ADCY3 Tiziana Cogliati, Christopher J. Westlake, Smo ARL13B F CEP290 Cell membrane Anand Swaroop I Gli2 B Cytoplasm R Other proteins O Correspondence Axoneme B Axoneme [email protected] (C.J.W.), L A [email protected] (A.S.) S Cell membrane Cell membrane T Vesicles In Brief Cytoplasm Cytoplasm Using fibroblasts and iPSC-derived optic Control CEP290-LCA cups from patients with distinct CEP290 mutations, Shimada et al. show a P H Cell membrane concordance between ciliogenesis O T ? defects in different cell types and clinical Axoneme ? O ? Axoneme ? Cytoplasm severity in Leber congenital amaurosis R ? Connecting Connecting ? E Cilium Cilium ? and Joubert syndrome. These studies Cell membrane C Cell membrane E establish CEP290 as gatekeeper of P Docked mother centriole T ?? ? ? signaling molecules in and out of the O primary cilium. R Cytoplasm Cytoplasm Highlights d Normal cilia in fibroblasts, but not in photoreceptors of CEP290-LCA organoids d No CEP290 protein and defective ciliogenesis in CEP290- JSRD fibroblasts d Selective reduction in ciliary localization of ARL13B and ADCY3 in JSRD fibroblasts d Cilia defects in JSRD fibroblasts affect Smo and GPR161 transport in Hh signaling Shimada et al., 2017, Cell Reports 20, 384–396 July 11, 2017 http://dx.doi.org/10.1016/j.celrep.2017.06.045 Cell Reports Article In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations Hiroko Shimada,1 Quanlong Lu,2 Christine Insinna-Kettenhofen,2 Kunio Nagashima,3 Milton A. English,1 Elizabeth M. Semler,2 Jacklyn Mahgerefteh,1 Artur V. Cideciyan,4 Tiansen Li,1 Brian P. Brooks,5 Meral Gunay-Aygun,6,7 Samuel G. Jacobson,4 Tiziana Cogliati,1 Christopher J. Westlake,2,* and Anand Swaroop1,8,* 1Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA 2Laboratory of Cell and Developmental Signaling 3Electron Microscope Laboratory, Leidos Biomedical Research, Inc. National Cancer Institute - Frederick, Frederick, MD 21702, USA 4Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 5Pediatric, Developmental, and Genetic Eye Disease Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA 6National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA 7Department of Pediatrics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 8Lead Contact *Correspondence: [email protected] (C.J.W.), [email protected] (A.S.) http://dx.doi.org/10.1016/j.celrep.2017.06.045 SUMMARY 2012). In non-dividing quiescent or post-mitotic differentiated cells, the mother centriole docks at the apical plasma mem- Mutations in CEP290, a transition zone protein in brane and forms the basal body (Ishikawa and Marshall, primary cilia, cause diverse ciliopathies, including 2011). The primary cilium originates from the basal body by spe- Leber congenital amaurosis (LCA) and Joubert-syn- cific targeting of hundreds of proteins along the ciliary axoneme drome and related disorders (JSRD). We examined via intraflagellar transport (IFT) (Pazour and Bloodgood, 2008; cilia biogenesis and function in cells derived from Boldt et al., 2016; Ishikawa et al., 2012; Sang et al., 2011). Not CEP290-LCA and CEP290-JSRD patients. CEP290 surprisingly, mutations in genes encoding ciliary proteins can cause a plethora of divergent yet overlapping clinical pheno- protein was reduced in LCA fibroblasts with no types (ciliopathies) (Hildebrandt et al., 2011; Nigg and Raff, detectable impact on cilia; however, optic cups 2009; Novarino et al., 2011). Clinical findings in Joubert syn- derived from induced pluripotent stem cells (iPSCs) drome (MIM: 213300) and related disorders (JSRD) include of CEP290-LCA patients displayed less developed fibrocystic disease of kidneys, retinal abnormalities, oculomo- photoreceptor cilia. Lack of CEP290 in JSRD fibro- tor apraxia, congenital hepatic fibrosis, and mental retardation blasts resulted in abnormal cilia and decreased cil- with malformation of cerebellar vermis and brainstem (Sattar iogenesis. We observed selectively reduced locali- and Gleeson, 2011). Retinopathy is commonly observed in syn- zation of ADCY3 and ARL13B. Notably, Hedgehog dromic ciliopathies, and photoreceptor degeneration caused by signaling was augmented in CEP290-JSRD because cilia defects in non-syndromic Leber congenital amaurosis of enhanced ciliary transport of Smoothened and (LCA) (MIM: 204000) represents the least severe phenotype GPR161. These results demonstrate a direct corre- (Rachel et al., 2012; Zaghloul and Katsanis, 2009). Initially identified for JSRD (Ben-Salem et al., 2014; Sayer lation between the extent of ciliogenesis defects et al., 2006; Valente et al., 2006), the centrosome-cilia gene in fibroblasts and photoreceptors with pheno- CEP290 is associated with multiple ciliopathy phenotypes (Cop- typic severity in JSRD and LCA, respectively, and pieters et al., 2010; Zaghloul and Katsanis, 2009). Subsequent to strengthen the role of CEP290 as a selective ciliary findings in a mouse retinal degeneration mutant (rd16) with hypo- gatekeeper for transport of signaling molecules in morphic Cep290 defect (Chang et al., 2006), mutations in and out of the cilium. CEP290 were discovered and now account for 20%–25% of LCA (den Hollander et al., 2006, 2008; Perrault et al., 2007). INTRODUCTION CEP290-LCA patients also exhibit additional sensory defects such as anosmia caused by olfactory cilia dysfunction (McEwen Primary cilia are highly conserved, non-motile microtubule- et al., 2007). based organelles that protrude from the surface of most verte- The CEP290 gene encodes a large multi-domain 290-kDa pro- brate cells and coordinate diverse sensory and developmental tein involved in cilia biogenesis and transport. The CEP290 pro- signaling pathways in different cell types and tissues (Goetz tein constitutes an integral component of the transition zone (TZ) and Anderson, 2010; Singla and Reiter, 2006; Oh and Katsanis, between the basal body and the ciliary axoneme and serves as a 384 Cell Reports 20, 384–396, July 11, 2017 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). diffusion barrier for transport in and out of the cilium (Craige tively). Phenotypes and genotypes of JSRD patients 1–3 are et al., 2010; Rachel et al., 2015). CEP290 is located in the Y- provided in Figure S2 and Table S1. All three JSRD patients shaped linker region of the TZ in photoreceptor cilium (Betleja had reduced visual acuity, moderate to high hyperopia, and Cole, 2010; Craige et al., 2010) and is necessary for the for- nystagmus, and retinal degeneration. JSRD patient 2 (JRSD-2) mation of the outer segment (Rachel et al., 2015), which is critical and JRSD-3 had coloboma. JSRD-3 also carried c.2501A > G; for phototransduction and cell survival (Gilliam et al., 2012; Mars- p.Gln834Arg variation in KIF7 and c.2882G > A; p.Arg961His zalek et al., 2000; Rachel et al., 2012; Tsujikawa and Malicki, change in NPHP4, which can potentially modify the JSRD 2004; Wright et al., 2010). Mutations in CEP290 are suggested phenotype caused by CEP290 mutations. to differentially impact protein interactions, cilia biogenesis, To establish a correlation between CEP290 mutation and the and trafficking in distinct cellular contexts. cilia phenotype, we examined CEP290 protein in fibroblasts by How specific CEP290 mutations generate a spectrum of over- immunoblot analysis. Full-length CEP290 protein was reduced lapping yet discrete pleiotropic effects in ciliopathies is poorly by 50%–80% in CEP290-LCA fibroblasts compared with understood. While LCA mutations associated with sensory controls; however, no protein was detected in CEP290-JSRD dysfunction (Chang et al., 2006; den Hollander et al., 2006; fibroblasts (Figures 1B and 1C). The splice donor site introduced McEwen et al., 2007) are likely hypomorphic, complex pheno- by the IVS26+1655A > G mutation competes with the normal types (such as JSRD) caused by wide-ranging human CEP290 splice donor site, leading to the production of variable amounts mutations are puzzling. Mouse Cep290 mutants can recapitulate of correctly spliced full-length CEP290 protein in LCA-1– several features associated with human disease; for example, an LCA-3. Full-length CEP290 protein levels were higher in LCA-3 in-frame deletion in Cep290 produces early photoreceptor fibroblasts carrying the homozygous IVS26+1655A > G allele degeneration in rd16 mice (Cideciyan et al., 2011), and Cep290 compared with LCA-1 and LCA-2 with the heterozygous gene-trap and knockout mice phenocopy syndromic ciliopathy IVS26+1655A > G allele, consistent with its being a hypomorphic (Hynes et al., 2014; Rachel et al., 2015). However, the precise mutation. All other heterozygous mutations in LCA and JSRD pa- biological impact of distinct human disease-causing CEP290 tients introduce either a premature stop codon (LCA-1, LCA-2, mutations remains unclear. JSRD-1, JSRD-2, and JSRD-3), a frameshift (JSRD-2), or an We took advantage of fibroblasts and induced pluripotent in-frame
Load more

Recommended publications
  • Unraveling the Genetics of Joubert and Meckel-Gruber Syndromes
    Journal of Pediatric Genetics 3 (2014) 65–78 65 DOI 10.3233/PGE-14090 IOS Press Unraveling the genetics of Joubert and Meckel-Gruber syndromes Katarzyna Szymanska, Verity L. Hartill and Colin A. Johnson∗ Department of Ophthalmology and Neuroscience, University of Leeds, Leeds, UK Received 27 May 2014 Revised 11 July 2014 Accepted 14 July 2014 Abstract. Joubert syndrome (JBTS) and Meckel-Gruber syndrome (MKS) are recessive neurodevelopmental conditions caused by mutations in proteins that are structural or functional components of the primary cilium. In this review, we provide an overview of their clinical diagnosis, management and molecular genetics. Both have variable phenotypes, extreme genetic heterogeneity, and display allelism both with each other and other ciliopathies. Recent advances in genetic technology have significantly improved diagnosis and clinical management of ciliopathy patients, with the delineation of some general genotype-phenotype correlations. We highlight those that are most relevant for clinical practice, including the correlation between TMEM67 mutations and the JBTS variant phenotype of COACH syndrome. The subcellular localization of the known MKS and JBTS proteins is now well-described, and we discuss some of the contemporary ideas about ciliopathy disease pathogenesis. Most JBTS and MKS proteins localize to a discrete ciliary compartment called the transition zone, and act as structural components of the so-called “ciliary gate” to regulate the ciliary trafficking of cargo proteins or lipids. Cargo proteins include enzymes and transmembrane proteins that mediate intracellular signaling. The disruption of transition zone function may contribute to the ciliopathy phenotype by altering the composition of the ciliary membrane or axoneme, with impacts on essential developmental signaling including the Wnt and Shh pathways as well as the regulation of secondary messengers such as inositol-1,4,5-trisphosphate (InsP3) and cyclic adenosine monophosphate (cAMP).
    [Show full text]
  • Prenatal Exome Sequencing in Anomalous Fetuses: New Opportunities and Challenges
    © American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Prenatal exome sequencing in anomalous fetuses: new opportunities and challenges Neeta L. Vora, MD1, Bradford Powell, MD, PhD2, Alicia Brandt, MS2, Natasha Strande, PhD3,4, Emily Hardisty, MS, CGC1, Kelly Gilmore, MS, CGC1, Ann Katherine M. Foreman, MS, CGC2,5, Kirk Wilhelmsen, MD, PhD6, Chris Bizon, PhD6, Jason Reilly, BA6, Phil Owen, BS6, Cynthia M. Powell, MD, MS2,7, Debra Skinner, PhD, MA8, Christine Rini, PhD9, Anne D. Lyerly, MD, MA10, Kim A. Boggess, MD1, Karen Weck, MD3,4, Jonathan S. Berg, MD, PhD2 and James P. Evans, MD, PhD2,10 Purpose: We investigated the diagnostic and clinical performance the following genes: COL1A1, MUSK, KCTD1, RTTN, TMEM67, of exome sequencing in fetuses with sonographic abnormalities PIEZO1 and DYNC2H1. One additional case revealed a de novo with normal karyotype and microarray and, in some cases, normal nonsense mutation in a novel candidate gene (MAP4K4). gene-specific sequencing. The perceived likelihood that exome sequencing would explain Methods: Exome sequencing was performed on DNA from 15 the results (5.2 on a 10-point scale) was higher than the anomalous fetuses and from the peripheral blood of their approximately 30% diagnostic yield discussed in pretest counseling. parents. Parents provided consent to be informed of diagnostic Conclusion: Exome sequencing had diagnostic utility in a highly results in the fetus, medically actionable findings in the parents, select population of fetuses where a genetic diagnosis was highly and their identification as carrier couples for significant auto- suspected. Challenges related to genetics literacy and variant somal recessive conditions.
    [Show full text]
  • Ciliopathies Gene Panel
    Ciliopathies Gene Panel Contact details Introduction Regional Genetics Service The ciliopathies are a heterogeneous group of conditions with considerable phenotypic overlap. Levels 4-6, Barclay House These inherited diseases are caused by defects in cilia; hair-like projections present on most 37 Queen Square cells, with roles in key human developmental processes via their motility and signalling functions. Ciliopathies are often lethal and multiple organ systems are affected. Ciliopathies are London, WC1N 3BH united in being genetically heterogeneous conditions and the different subtypes can share T +44 (0) 20 7762 6888 many clinical features, predominantly cystic kidney disease, but also retinal, respiratory, F +44 (0) 20 7813 8578 skeletal, hepatic and neurological defects in addition to metabolic defects, laterality defects and polydactyly. Their clinical variability can make ciliopathies hard to recognise, reflecting the ubiquity of cilia. Gene panels currently offer the best solution to tackling analysis of genetically Samples required heterogeneous conditions such as the ciliopathies. Ciliopathies affect approximately 1:2,000 5ml venous blood in plastic EDTA births. bottles (>1ml from neonates) Ciliopathies are generally inherited in an autosomal recessive manner, with some autosomal Prenatal testing must be arranged dominant and X-linked exceptions. in advance, through a Clinical Genetics department if possible. Referrals Amniotic fluid or CV samples Patients presenting with a ciliopathy; due to the phenotypic variability this could be a diverse set should be sent to Cytogenetics for of features. For guidance contact the laboratory or Dr Hannah Mitchison dissecting and culturing, with ([email protected]) / Prof Phil Beales ([email protected]) instructions to forward the sample to the Regional Molecular Genetics Referrals will be accepted from clinical geneticists and consultants in nephrology, metabolic, laboratory for analysis respiratory and retinal diseases.
    [Show full text]
  • Perkinelmer Genomics to Request the Saliva Swab Collection Kit for Patients That Cannot Provide a Blood Sample As Whole Blood Is the Preferred Sample
    Eye Disorders Comprehensive Panel Test Code D4306 Test Summary This test analyzes 211 genes that have been associated with ocular disorders. Turn-Around-Time (TAT)* 3 - 5 weeks Acceptable Sample Types Whole Blood (EDTA) (Preferred sample type) DNA, Isolated Dried Blood Spots Saliva Acceptable Billing Types Self (patient) Payment Institutional Billing Commercial Insurance Indications for Testing Individuals with an eye disease suspected to be genetic in origin Individuals with a family history of eye disease Individuals suspected to have a syndrome associated with an eye disease Test Description This panel analyzes 211 genes that have been associated with ocular disorders. Both sequencing and deletion/duplication (CNV) analysis will be performed on the coding regions of all genes included (unless otherwise marked). All analysis is performed utilizing Next Generation Sequencing (NGS) technology. CNV analysis is designed to detect the majority of deletions and duplications of three exons or greater in size. Smaller CNV events may also be detected and reported, but additional follow-up testing is recommended if a smaller CNV is suspected. All variants are classified according to ACMG guidelines. Condition Description Diseases associated with this panel include microphtalmia, anophthalmia, coloboma, progressive external ophthalmoplegia, optic nerve atrophy, retinal dystrophies, retinitis pigementosa, macular degeneration, flecked-retinal disorders, Usher syndrome, albinsm, Aloprt syndrome, Bardet Biedl syndrome, pulmonary fibrosis, and Hermansky-Pudlak
    [Show full text]
  • Interpreting TMEM67 Missense Variants of Uncertain
    bioRxiv preprint doi: https://doi.org/10.1101/2021.06.17.448799; this version posted June 17, 2021. 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 4.0 International license. 1 Interpreting TMEM67‌ missense‌ variants‌ of‌ uncertain‌ significance‌ (VUS) ‌ in ‌‌ 2 an‌ animal‌ model‌ ‌ 3 4 Karen I. Lange1* , Sunayna Best 2, Sofia Tsiropoulou1 , Ian Berry 3, Colin A. Johnson 2, Oliver E. 5 Blacque 1* 6 7 1. School‌ of‌ Biomolecular‌ and Biomedical‌ Science, Conway‌ Institute, University‌ College‌ Dublin,‌ Ireland. 8 2. Division of‌ Molecular‌ Medicine, Leeds‌ Institute‌ of‌ Medical‌ Research,‌ University‌ of‌ Leeds, Leeds, West ‌ 9 Yorkshire, UK. 10 3. Bristol‌ Genetics‌ Laboratory, Pathology‌ Sciences, Southmead Hospital, Bristol, BS10 5NB, UK. 11 12 * Correspondence to [email protected], [email protected] 13 14 Keywords: C. elegans, CRISPR, TMEM67, mks-3 , Meckelin, disease modelling, VUS ‌ 15 interpretation, ciliopathy, Meckel Syndrome, Joubert Syndrome, COACH. 16 17 ABSTRACT 18 19 Purpose: A molecular genetic diagnosis is essential for accurate counselling and management 20 of patients with ciliopathies. Uncharacterized missense alleles are often classified as variants 21 of uncertain significance (VUS) and are not clinically useful. In this study, we explore the use ‌ 22 of a tractable animal model ( C. elegans ) for in vivo interpretation of missense VUS alleles of ‌ 23 TMEM67 , a gene frequently mutated as a cause of ciliopathies. 24 Methods: CRISPR/Cas9 gene editing was used to generate homozygous worm strains ‌ 25 carrying TMEM67 patient variants. Quantitative phenotypic assays (dye filling, roaming, ‌ 26 chemotaxis) assessed cilia structure and function. Results were validated by genetic 27 complementation assays in a human TMEM67 knock-out hTERT-RPE1 cell line.
    [Show full text]
  • Novel TMEM67 Mutations and Genotype?Phenotype Correlates In
    HUMAN MUTATION Mutation in Brief 31: E1319-E1331 (2010) Online MUTATION IN BRIEF HUMAN MUTATION OFFICIAL JOURNAL Novel TMEM67 Mutations and Genotype-phenotype Correlates in Meckelin-related Ciliopathies www.hgvs.org Miriam Iannicelli,1# Francesco Brancati,1,2# Soumaya Mougou-Zerelli,3 Annalisa Mazzotta,1 Sophie Thomas,3 Nadia Elkhartoufi,4 Lorena Travaglini,1 Céline Gomes,3 Gian Luigi Ardissino,5 Enrico Bertini,6 Eugen Boltshauser,7 Pierangela Castorina,5 Stefano D’Arrigo,8 Rita Fischetto,9 Brigitte Leroy,10 Philippe Loget,11 Maryse Bonnière,12 Lena Starck,13 Julia Tantau,14 Barbara Gentilin,5 Silvia Majore,15 Dominika Swistun,16 Elizabeth Flori,17 Faustina Lalatta,5 Chiara Pantaleoni,8 Johannes.Penzien,18 Paola Grammatico,15 the International JSRD Study Group, Bruno Dallapiccola,6 Joseph G. Gleeson,16 Tania Attie-Bitach,3,4* and Enza Maria Valente,1,19* 1Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo and CSS-Mendel Institute, Rome, Italy; 2CeSI, Aging Research Centre, and Dept. of Biomedical Sciences, G. d’Annunzio University Foundation, Chieti, Italy; 3INSERM U-781, Hôpital Necker-Enfants Malades and Université René Descartes, Paris V, France; 4Dept of Genetics, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (APHP), Paris, France; 5Foundation IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milan, Italy; 6 IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy; 7Dept. of Neurology, Children's University Hospital, Zurich, Switzerland; 8Division of Neurologia dello Sviluppo, Carlo Besta Neurologic Institute Foundation, Milan, Italy; 9UO Metabolic Disease-Medical Genetics, PO Giovanni XXIII-AOU Policlinico Consorziale, Bari, Italy;10Service d’Anatomie et Cytologie Pathologiques, CHI de Poissy, Saint Germain-en-Laye; 11Cabinet d’Anatomie et Cytologie Pathologiques Richier, Rennes, France;12Anatomopathologie, Lille, France; 13Sachs´Children´s Hospital, Stockholm,Sweden; 14Service d’Anatomopathologie, Hôpital Saint-Vincent de Paul, AP-HP, Paris; 15 Dept.
    [Show full text]
  • Supplementary Information – Postema Et Al., the Genetics of Situs Inversus Totalis Without Primary Ciliary Dyskinesia
    1 Supplementary information – Postema et al., The genetics of situs inversus totalis without primary ciliary dyskinesia Table of Contents: Supplementary Methods 2 Supplementary Results 5 Supplementary References 6 Supplementary Tables and Figures Table S1. Subject characteristics 9 Table S2. Inbreeding coefficients per subject 10 Figure S1. Multidimensional scaling to capture overall genomic diversity 11 among the 30 study samples Table S3. Significantly enriched gene-sets under a recessive mutation model 12 Table S4. Broader list of candidate genes, and the sources that led to their 13 inclusion Table S5. Potential recessive and X-linked mutations in the unsolved cases 15 Table S6. Potential mutations in the unsolved cases, dominant model 22 2 1.0 Supplementary Methods 1.1 Participants Fifteen people with radiologically documented SIT, including nine without PCD and six with Kartagener syndrome, and 15 healthy controls matched for age, sex, education and handedness, were recruited from Ghent University Hospital and Middelheim Hospital Antwerp. Details about the recruitment and selection procedure have been described elsewhere (1). Briefly, among the 15 people with radiologically documented SIT, those who had symptoms reminiscent of PCD, or who were formally diagnosed with PCD according to their medical record, were categorized as having Kartagener syndrome. Those who had no reported symptoms or formal diagnosis of PCD were assigned to the non-PCD SIT group. Handedness was assessed using the Edinburgh Handedness Inventory (EHI) (2). Tables 1 and S1 give overviews of the participants and their characteristics. Note that one non-PCD SIT subject reported being forced to switch from left- to right-handedness in childhood, in which case five out of nine of the non-PCD SIT cases are naturally left-handed (Table 1, Table S1).
    [Show full text]
  • A Systems-Genetics Analyses of Complex Phenotypes
    A systems-genetics analyses of complex phenotypes A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Life Sciences 2015 David Ashbrook Table of contents Table of contents Table of contents ............................................................................................... 1 Tables and figures ........................................................................................... 10 General abstract ............................................................................................... 14 Declaration ....................................................................................................... 15 Copyright statement ........................................................................................ 15 Acknowledgements.......................................................................................... 16 Chapter 1: General introduction ...................................................................... 17 1.1 Overview................................................................................................... 18 1.2 Linkage, association and gene annotations .............................................. 20 1.3 ‘Big data’ and ‘omics’ ................................................................................ 22 1.4 Systems-genetics ..................................................................................... 24 1.5 Recombinant inbred (RI) lines and the BXD .............................................. 25 Figure 1.1:
    [Show full text]
  • Whole-Exome Sequencing Identifies Causative Mutations in Families
    BASIC RESEARCH www.jasn.org Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract Amelie T. van der Ven,1 Dervla M. Connaughton,1 Hadas Ityel,1 Nina Mann,1 Makiko Nakayama,1 Jing Chen,1 Asaf Vivante,1 Daw-yang Hwang,1 Julian Schulz,1 Daniela A. Braun,1 Johanna Magdalena Schmidt,1 David Schapiro,1 Ronen Schneider,1 Jillian K. Warejko,1 Ankana Daga,1 Amar J. Majmundar,1 Weizhen Tan,1 Tilman Jobst-Schwan,1 Tobias Hermle,1 Eugen Widmeier,1 Shazia Ashraf,1 Ali Amar,1 Charlotte A. Hoogstraaten,1 Hannah Hugo,1 Thomas M. Kitzler,1 Franziska Kause,1 Caroline M. Kolvenbach,1 Rufeng Dai,1 Leslie Spaneas,1 Kassaundra Amann,1 Deborah R. Stein,1 Michelle A. Baum,1 Michael J.G. Somers,1 Nancy M. Rodig,1 Michael A. Ferguson,1 Avram Z. Traum,1 Ghaleb H. Daouk,1 Radovan Bogdanovic,2 Natasa Stajic,2 Neveen A. Soliman,3,4 Jameela A. Kari,5,6 Sherif El Desoky,5,6 Hanan M. Fathy,7 Danko Milosevic,8 Muna Al-Saffar,1,9 Hazem S. Awad,10 Loai A. Eid,10 Aravind Selvin,11 Prabha Senguttuvan,12 Simone Sanna-Cherchi,13 Heidi L. Rehm,14 Daniel G. MacArthur,14,15 Monkol Lek,14,15 Kristen M. Laricchia,15 Michael W. Wilson,15 Shrikant M. Mane,16 Richard P. Lifton,16,17 Richard S. Lee,18 Stuart B. Bauer,18 Weining Lu,19 Heiko M. Reutter ,20,21 Velibor Tasic,22 Shirlee Shril,1 and Friedhelm Hildebrandt1 Due to the number of contributing authors, the affiliations are listed at the end of this article.
    [Show full text]
  • Cystic Kidney Diseases and During Vertebrate Gastrulation
    Pediatr Nephrol (2011) 26:1181–1195 DOI 10.1007/s00467-010-1697-5 REVIEW Cystic diseases of the kidney: ciliary dysfunction and cystogenic mechanisms Cecilia Gascue & Nicholas Katsanis & Jose L. Badano Received: 3 August 2010 /Revised: 15 September 2010 /Accepted: 15 October 2010 /Published online: 27 November 2010 # IPNA 2010 Abstract Ciliary dysfunction has emerged as a common Introduction factor underlying the pathogenesis of both syndromic and isolated kidney cystic disease, an observation that has Cystic diseases of the kidney are a significant contributor to contributed to the unification of human genetic disorders of renal malformations and a common cause of end stage renal the cilium, the ciliopathies. Such grouping is underscored disease (ESRD). This classification encompasses a number by two major observations: the fact that genes encoding of human disorders that range from conditions in which ciliary proteins can contribute causal and modifying cyst formation is either the sole or the main clinical mutations across several clinically discrete ciliopathies, manifestation, to pleiotropic syndromes where cyst forma- and the emerging realization that an understanding of the tion is but one of the observed pathologies, exhibits clinical pathology of one ciliopathy can provide valuable variable penetrance, and can sometimes be undetectable insight into the pathomechanism of renal cyst formation until later in life or upon necropsy (Table 1;[1]). elsewhere in the ciliopathy spectrum. In this review, we Importantly, although the different cystic kidney disorders discuss and attempt to stratify the different lines of are clinically discrete entities, an extensive body of data proposed cilia-driven mechanisms for cystogenesis, ranging fueled by a combination of mutation identification in from mechano- and chemo-sensation, to cell shape and humans and studies in animal models suggests a common polarization, to the transduction of a variety of signaling thread, where virtually all known renal cystic disease- cascades.
    [Show full text]
  • Ciliopathies
    T h e new england journal o f medicine Review article Mechanisms of Disease Robert S. Schwartz, M.D., Editor Ciliopathies Friedhelm Hildebrandt, M.D., Thomas Benzing, M.D., and Nicholas Katsanis, Ph.D. iverse developmental and degenerative single-gene disor- From the Howard Hughes Medical Insti- ders such as polycystic kidney disease, nephronophthisis, retinitis pigmen- tute and the Departments of Pediatrics and Human Genetics, University of Michi- tosa, the Bardet–Biedl syndrome, the Joubert syndrome, and the Meckel gan Health System, Ann Arbor (F.H.); the D Renal Division, Department of Medicine, syndrome may be categorized as ciliopathies — a recent concept that describes dis- eases characterized by dysfunction of a hairlike cellular organelle called the cilium. Center for Molecular Medicine, and Co- logne Cluster of Excellence in Cellular Most of the proteins that are altered in these single-gene disorders function at the Stress Responses in Aging-Associated Dis- level of the cilium–centrosome complex, which represents nature’s universal system eases, University of Cologne, Cologne, for cellular detection and management of external signals. Cilia are microtubule- Germany (T.B.); and the Center for Hu- man Disease Modeling and the Depart- based structures found on almost all vertebrate cells. They originate from a basal ments of Pediatrics and Cell Biology, body, a modified centrosome, which is the organelle that forms the spindle poles Duke University Medical Center, Durham, during mitosis. The important role that the cilium–centrosome complex plays in NC (N.K.). Address reprint requests to Dr. Hildebrandt at Howard Hughes Med- the normal function of most tissues appears to account for the involvement of mul- ical Institute, Departments of Pediatrics tiple organ systems in ciliopathies.
    [Show full text]
  • Ciliary Genes in Renal Cystic Diseases
    cells Review Ciliary Genes in Renal Cystic Diseases Anna Adamiok-Ostrowska * and Agnieszka Piekiełko-Witkowska * Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland * Correspondence: [email protected] (A.A.-O.); [email protected] (A.P.-W.); Tel.: +48-22-569-3810 (A.P.-W.) Received: 3 March 2020; Accepted: 5 April 2020; Published: 8 April 2020 Abstract: Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.
    [Show full text]