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Educational Paper Ciliopathies
Eur J Pediatr (2012) 171:1285–1300 DOI 10.1007/s00431-011-1553-z REVIEW Educational paper Ciliopathies Carsten Bergmann Received: 11 June 2011 /Accepted: 3 August 2011 /Published online: 7 September 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract Cilia are antenna-like organelles found on the (NPHP) . Ivemark syndrome . Meckel syndrome (MKS) . surface of most cells. They transduce molecular signals Joubert syndrome (JBTS) . Bardet–Biedl syndrome (BBS) . and facilitate interactions between cells and their Alstrom syndrome . Short-rib polydactyly syndromes . environment. Ciliary dysfunction has been shown to Jeune syndrome (ATD) . Ellis-van Crefeld syndrome (EVC) . underlie a broad range of overlapping, clinically and Sensenbrenner syndrome . Primary ciliary dyskinesia genetically heterogeneous phenotypes, collectively (Kartagener syndrome) . von Hippel-Lindau (VHL) . termed ciliopathies. Literally, all organs can be affected. Tuberous sclerosis (TSC) . Oligogenic inheritance . Modifier. Frequent cilia-related manifestations are (poly)cystic Mutational load kidney disease, retinal degeneration, situs inversus, cardiac defects, polydactyly, other skeletal abnormalities, and defects of the central and peripheral nervous Introduction system, occurring either isolated or as part of syn- dromes. Characterization of ciliopathies and the decisive Defective cellular organelles such as mitochondria, perox- role of primary cilia in signal transduction and cell isomes, and lysosomes are well-known -
Ciliopathiesneuromuscularciliopathies Disorders Disorders Ciliopathiesciliopathies
NeuromuscularCiliopathiesNeuromuscularCiliopathies Disorders Disorders CiliopathiesCiliopathies AboutAbout EGL EGL Genet Geneticsics EGLEGL Genetics Genetics specializes specializes in ingenetic genetic diagnostic diagnostic testing, testing, with with ne nearlyarly 50 50 years years of of clinical clinical experience experience and and board-certified board-certified labor laboratoryatory directorsdirectors and and genetic genetic counselors counselors reporting reporting out out cases. cases. EGL EGL Genet Geneticsics offers offers a combineda combined 1000 1000 molecular molecular genetics, genetics, biochemical biochemical genetics,genetics, and and cytogenetics cytogenetics tests tests under under one one roof roof and and custom custom test testinging for for all all medically medically relevant relevant genes, genes, for for domestic domestic andand international international clients. clients. EquallyEqually important important to to improving improving patient patient care care through through quality quality genetic genetic testing testing is is the the contribution contribution EGL EGL Genetics Genetics makes makes back back to to thethe scientific scientific and and medical medical communities. communities. EGL EGL Genetics Genetics is is one one of of only only a afew few clinical clinical diagnostic diagnostic laboratories laboratories to to openly openly share share data data withwith the the NCBI NCBI freely freely available available public public database database ClinVar ClinVar (>35,000 (>35,000 variants variants on on >1700 >1700 genes) genes) and and is isalso also the the only only laboratory laboratory with with a a frefree oen olinnlein dea dtabtaabsaes (eE m(EVmCVlaCslas)s,s f)e, afetuatruinrgin ag vaa vraiarniatn ctl acslasisfiscifiactiaotino sne saercahrc ahn adn rde rpeoprot rrte rqeuqeuset sint tinetrefarcfaec, ew, hwichhic fha cfailcitialiteatse rsa praidp id interactiveinteractive curation curation and and reporting reporting of of variants. -
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. -
Establishment of the Early Cilia Preassembly Protein Complex
Establishment of the early cilia preassembly protein PNAS PLUS complex during motile ciliogenesis Amjad Horania,1, Alessandro Ustioneb, Tao Huangc, Amy L. Firthd, Jiehong Panc, Sean P. Gunstenc, Jeffrey A. Haspelc, David W. Pistonb, and Steven L. Brodyc aDepartment of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110; bDepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; cDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and dDepartment of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033 Edited by Kathryn V. Anderson, Sloan Kettering Institute, New York, NY, and approved December 27, 2017 (received for review September 9, 2017) Motile cilia are characterized by dynein motor units, which preas- function of these proteins is unknown; however, missing dynein semble in the cytoplasm before trafficking into the cilia. Proteins motor complexes in the cilia of mutants and cytoplasmic locali- required for dynein preassembly were discovered by finding human zation (or absence in the cilia proteome) suggest a role in the mutations that result in absent ciliary motors, but little is known preassembly of dynein motor complexes. Studies in C. reinhardtii about their expression, function, or interactions. By monitoring show motor components in the cell body before transport to ciliogenesis in primary airway epithelial cells and MCIDAS-regulated flagella (22–25). However, the expression, interactions, and induced pluripotent stem cells, we uncovered two phases of expres- functions of preassembly proteins, as well as the steps required sion of preassembly proteins. An early phase, composed of HEATR2, for preassembly, are undefined. -
Next Generation Massively Parallel Sequencing of Targeted
ARTICLE Next generation massively parallel sequencing of targeted exomes to identify genetic mutations in primary ciliary dyskinesia: Implications for application to clinical testing Jonathan S. Berg, MD, PhD1,2, James P. Evans, MD, PhD1,2, Margaret W. Leigh, MD3, Heymut Omran, MD4, Chris Bizon, PhD5, Ketan Mane, PhD5, Michael R. Knowles, MD2, Karen E. Weck, MD1,6, and Maimoona A. Zariwala, PhD6 Purpose: Advances in genetic sequencing technology have the potential rimary ciliary dyskinesia (PCD) is an autosomal recessive to enhance testing for genes associated with genetically heterogeneous Pdisorder involving abnormalities of motile cilia, resulting in clinical syndromes, such as primary ciliary dyskinesia. The objective of a range of manifestations including situs inversus, neonatal this study was to investigate the performance characteristics of exon- respiratory distress at full-term birth, recurrent otitis media, capture technology coupled with massively parallel sequencing for chronic sinusitis, chronic bronchitis that may result in bronchi- 1–3 clinical diagnostic evaluation. Methods: We performed a pilot study of ectasis, and male infertility. The disorder is genetically het- four individuals with a variety of previously identified primary ciliary erogeneous, rendering molecular diagnosis challenging given dyskinesia mutations. We designed a custom array (NimbleGen) to that mutations in nine different genes (DNAH5, DNAH11, capture 2089 exons from 79 genes associated with primary ciliary DNAI1, DNAI2, KTU, LRRC50, RSPH9, RSPH4A, and TX- dyskinesia or ciliary function and sequenced the enriched material using NDC3) account for only approximately 1/3 of PCD cases.4 the GS FLX Titanium (Roche 454) platform. Bioinformatics analysis DNAH5 and DNAI1 account for the majority of known muta- was performed in a blinded fashion in an attempt to detect the previ- tions, and the other genes each account for a small number of ously identified mutations and validate the process. -
Mackenzie's Mission Gene & Condition List
Mackenzie’s Mission Gene & Condition List What conditions are being screened for in Mackenzie’s Mission? Genetic carrier screening offered through this research study has been carefully developed. It is focused on providing people with information about their chance of having children with a severe genetic condition occurring in childhood. The screening is designed to provide genetic information that is relevant and useful, and to minimise uncertain and unclear information. How the conditions and genes are selected The Mackenzie’s Mission reproductive genetic carrier screen currently includes approximately 1300 genes which are associated with about 750 conditions. The reason there are fewer conditions than genes is that some genetic conditions can be caused by changes in more than one gene. The gene list is reviewed regularly. To select the conditions and genes to be screened, a committee comprised of experts in genetics and screening was established including: clinical geneticists, genetic scientists, a genetic pathologist, genetic counsellors, an ethicist and a parent of a child with a genetic condition. The following criteria were developed and are used to select the genes to be included: • Screening the gene is technically possible using currently available technology • The gene is known to cause a genetic condition • The condition affects people in childhood • The condition has a serious impact on a person’s quality of life and/or is life-limiting o For many of the conditions there is no treatment or the treatment is very burdensome for the child and their family. For some conditions very early diagnosis and treatment can make a difference for the child. -
Centometabolic® COMBINING GENETIC and BIOCHEMICAL TESTING for the FAST and COMPREHENSIVE DIAGNOSTIC of METABOLIC DISORDERS
CentoMetabolic® COMBINING GENETIC AND BIOCHEMICAL TESTING FOR THE FAST AND COMPREHENSIVE DIAGNOSTIC OF METABOLIC DISORDERS GENE ASSOCIATED DISEASE(S) ABCA1 HDL deficiency, familial, 1; Tangier disease ABCB4 Cholestasis, progressive familial intrahepatic 3 ABCC2 Dubin-Johnson syndrome ABCD1 Adrenoleukodystrophy; Adrenomyeloneuropathy, adult ABCD4 Methylmalonic aciduria and homocystinuria, cblJ type ABCG5 Sitosterolemia 2 ABCG8 Sitosterolemia 1 ACAT1 Alpha-methylacetoacetic aciduria ADA Adenosine deaminase deficiency AGA Aspartylglucosaminuria AGL Glycogen storage disease IIIa; Glycogen storage disease IIIb AGPS Rhizomelic chondrodysplasia punctata, type 3 AGXT Hyperoxaluria, primary, type 1 ALAD Porphyria, acute hepatic ALAS2 Anemia, sideroblastic, 1; Protoporphyria, erythropoietic, X-linked ALDH4A1 Hyperprolinemia, type II ALDOA Glycogen storage disease XII ALDOB Fructose intolerance, hereditary ALG3 Congenital disorder of glycosylation, type Id ALPL Hypophosphatasia, adult; Hypophosphatasia, childhood; Hypophosphatasia, infantile; Odontohypophosphatasia ANTXR2 Hyaline fibromatosis syndrome APOA2 Hypercholesterolemia, familial, modifier of APOA5 Hyperchylomicronemia, late-onset APOB Hypercholesterolemia, familial, 2 APOC2 Hyperlipoproteinemia, type Ib APOE Sea-blue histiocyte disease; Hyperlipoproteinemia, type III ARG1 Argininemia ARSA Metachromatic leukodystrophy ARSB Mucopolysaccharidosis type VI (Maroteaux-Lamy) 1 GENE ASSOCIATED DISEASE(S) ASAH1 Farber lipogranulomatosis; Spinal muscular atrophy with progressive myoclonic epilepsy -
Ciliary Dyneins and Dynein Related Ciliopathies
cells Review Ciliary Dyneins and Dynein Related Ciliopathies Dinu Antony 1,2,3, Han G. Brunner 2,3 and Miriam Schmidts 1,2,3,* 1 Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Mathildenstrasse 1, 79106 Freiburg, Germany; [email protected] 2 Genome Research Division, Human Genetics Department, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 KL Nijmegen, The Netherlands; [email protected] 3 Radboud Institute for Molecular Life Sciences (RIMLS), Geert Grooteplein Zuid 10, 6525 KL Nijmegen, The Netherlands * Correspondence: [email protected]; Tel.: +49-761-44391; Fax: +49-761-44710 Abstract: Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel Citation: Antony, D.; Brunner, H.G.; developments in the field. -
IFM) Analysis of Primary Ciliary Dyskinesia (PCD) Patients with Suspected Inner Dynein Arm Defects (IDA
Hjeij et al. Cilia 2012, 1(Suppl 1):P23 http://www.ciliajournal.com/content/1/S1/P23 POSTERPRESENTATION Open Access Immunofluorescence microscopy (IFM) analysis of primary ciliary dyskinesia (PCD) patients with suspected inner dynein arm defects (IDA) R Hjeij1*, NT Loges1, A Becker-Heck2, H Omran1 From First International Cilia in Development and Disease Scientific Conference (2012) London, UK. 16-18 May 2012 Primary ciliary dyskinesia (PCD), characterized by abnor- Author details 1Universitätsklinikum Münster, Germany. 2Department of Pediatrics, University mal motility of cilia or flagella, is caused by defects of Hospital Freiburg, Germany. structural components such as inner dynein arms (IDAs). Recently high-speed videomicroscopy has substituted Published: 16 November 2012 transmission electron microscopy (TEM) analysis as the “gold standard” for diagnosis. However, TEM is still the most widely used diagnostic tool in many countries. A doi:10.1186/2046-2530-1-S1-P23 Cite this article as: Hjeij et al.: Immunofluorescence microscopy (IFM) recent study reported that isolated IDA defects is the most analysis of primary ciliary dyskinesia (PCD) patients with suspected frequent (> 50%) ciliary defect in PCD, as detected by inner dynein arm defects (IDA). Cilia 2012 1(Suppl 1):P23. TEM (Theegarten, 2011). IFM analysis has shown in several studies that it can ascertain diagnosis such as in PCD variants caused by DNAH5, DNAI1, DNAI2, KTU, LRRC50, CCDC39 and CCDC40 mutations. IFM can pro- vide a complete view of the ciliary axoneme and identify “partial” axonemal defects which may be misinterpreted by TEM (e.g. present in KTU mutant cilia). Here we per- formed IFM analysis of known PCD patients to identify the composition of dynein arm defects, including IDAs. -
Identification and Classification of Novel Genetic Variants
International Journal of Molecular Sciences Article Identification and Classification of Novel Genetic Variants: En Route to the Diagnosis of Primary Ciliary Dyskinesia Nina Stevanovic 1, Anita Skakic 1, Predrag Minic 2,3, Aleksandar Sovtic 2 , Maja Stojiljkovic 1, Sonja Pavlovic 1 and Marina Andjelkovic 1,* 1 Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11010 Belgrade, Serbia; [email protected] (N.S.); [email protected] (A.S.); [email protected] (M.S.); [email protected] (S.P.) 2 Mother and Child Health Care Institute of Serbia Dr. VukanCupic, 11070 Belgrade, Serbia; [email protected] (P.M.); [email protected] (A.S.) 3 School of Medicine, University of Belgrade, 11000 Belgrade, Serbia * Correspondence: [email protected]; Tel.: +381-64-2202-373; Fax: +381-11-3975-808 Abstract: Primary ciliary dyskinesia (PCD) is a disease caused by impaired function of motile cilia. PCD mainly affects the lungs and reproductive organs. Inheritance is autosomal recessive and X-linked. PCD patients have diverse clinical manifestations, thus making the establishment of proper diagnosis challenging. The utility of next-generation sequencing (NGS) technology for diagnostic purposes allows for better understanding of the PCD genetic background. However, identification of specific disease-causing variants is difficult. The main aim of this study was to create a unique Citation: Stevanovic, N.; Skakic, A.; guideline that will enable the standardization of the assessment of novel genetic variants within PCD- Minic, P.; Sovtic, A.; Stojiljkovic, M.; associated genes. The designed pipeline consists of three main steps: (1) sequencing, detection, and Pavlovic, S.; Andjelkovic, M. -
Supplementary Table 1
Supplementary Table 1. 492 genes are unique to 0 h post-heat timepoint. The name, p-value, fold change, location and family of each gene are indicated. Genes were filtered for an absolute value log2 ration 1.5 and a significance value of p ≤ 0.05. Symbol p-value Log Gene Name Location Family Ratio ABCA13 1.87E-02 3.292 ATP-binding cassette, sub-family unknown transporter A (ABC1), member 13 ABCB1 1.93E-02 −1.819 ATP-binding cassette, sub-family Plasma transporter B (MDR/TAP), member 1 Membrane ABCC3 2.83E-02 2.016 ATP-binding cassette, sub-family Plasma transporter C (CFTR/MRP), member 3 Membrane ABHD6 7.79E-03 −2.717 abhydrolase domain containing 6 Cytoplasm enzyme ACAT1 4.10E-02 3.009 acetyl-CoA acetyltransferase 1 Cytoplasm enzyme ACBD4 2.66E-03 1.722 acyl-CoA binding domain unknown other containing 4 ACSL5 1.86E-02 −2.876 acyl-CoA synthetase long-chain Cytoplasm enzyme family member 5 ADAM23 3.33E-02 −3.008 ADAM metallopeptidase domain Plasma peptidase 23 Membrane ADAM29 5.58E-03 3.463 ADAM metallopeptidase domain Plasma peptidase 29 Membrane ADAMTS17 2.67E-04 3.051 ADAM metallopeptidase with Extracellular other thrombospondin type 1 motif, 17 Space ADCYAP1R1 1.20E-02 1.848 adenylate cyclase activating Plasma G-protein polypeptide 1 (pituitary) receptor Membrane coupled type I receptor ADH6 (includes 4.02E-02 −1.845 alcohol dehydrogenase 6 (class Cytoplasm enzyme EG:130) V) AHSA2 1.54E-04 −1.6 AHA1, activator of heat shock unknown other 90kDa protein ATPase homolog 2 (yeast) AK5 3.32E-02 1.658 adenylate kinase 5 Cytoplasm kinase AK7 -
Pili Torti: a Feature of Numerous Congenital and Acquired Conditions
Journal of Clinical Medicine Review Pili Torti: A Feature of Numerous Congenital and Acquired Conditions Aleksandra Hoffmann 1 , Anna Wa´skiel-Burnat 1,*, Jakub Z˙ ółkiewicz 1 , Leszek Blicharz 1, Adriana Rakowska 1, Mohamad Goldust 2 , Małgorzata Olszewska 1 and Lidia Rudnicka 1 1 Department of Dermatology, Medical University of Warsaw, Koszykowa 82A, 02-008 Warsaw, Poland; [email protected] (A.H.); [email protected] (J.Z.);˙ [email protected] (L.B.); [email protected] (A.R.); [email protected] (M.O.); [email protected] (L.R.) 2 Department of Dermatology, University Medical Center of the Johannes Gutenberg University, 55122 Mainz, Germany; [email protected] * Correspondence: [email protected]; Tel.: +48-22-5021-324; Fax: +48-22-824-2200 Abstract: Pili torti is a rare condition characterized by the presence of the hair shaft, which is flattened at irregular intervals and twisted 180◦ along its long axis. It is a form of hair shaft disorder with increased fragility. The condition is classified into inherited and acquired. Inherited forms may be either isolated or associated with numerous genetic diseases or syndromes (e.g., Menkes disease, Björnstad syndrome, Netherton syndrome, and Bazex-Dupré-Christol syndrome). Moreover, pili torti may be a feature of various ectodermal dysplasias (such as Rapp-Hodgkin syndrome and Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome). Acquired pili torti was described in numerous forms of alopecia (e.g., lichen planopilaris, discoid lupus erythematosus, dissecting Citation: Hoffmann, A.; cellulitis, folliculitis decalvans, alopecia areata) as well as neoplastic and systemic diseases (such Wa´skiel-Burnat,A.; Zółkiewicz,˙ J.; as cutaneous T-cell lymphoma, scalp metastasis of breast cancer, anorexia nervosa, malnutrition, Blicharz, L.; Rakowska, A.; Goldust, M.; Olszewska, M.; Rudnicka, L.