DOCSLIB.ORG

Emerging Genotype-Phenotype Relationships in Primary Ciliary Dyskinesia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Emerging Genotype-Phenotype Relationships in Primary Ciliary Dyskinesia International Journal of Molecular Sciences Review Emerging Genotype-Phenotype Relationships in Primary Ciliary Dyskinesia Steven K Brennan 1,* , Thomas W Ferkol 1 and Stephanie D Davis 2 1 Department of Pediatrics, Division of Allergy and Pulmonary Medicine, Campus Box 8116, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA; [email protected] 2 Department of Pediatrics, University of North Carolina School of Medicine, 101 Manning Drive, Chapel Hill, NC 27514, USA; [email protected] * Correspondence: [email protected] Abstract: Primary ciliary dyskinesia (PCD) is a rare inherited condition affecting motile cilia and leading to organ laterality defects, recurrent sino-pulmonary infections, bronchiectasis, and severe lung disease. Research over the past twenty years has revealed variability in clinical presentations, ranging from mild to more severe phenotypes. Genotype and phenotype relationships have emerged. The increasing availability of genetic panels for PCD continue to redefine these genotype-phenotype relationships and reveal milder forms of disease that had previously gone unrecognized. Keywords: primary ciliary dyskinesia; molecular genetics; genotype-phenotype association Citation: Brennan, S.K.; Ferkol, T.W.; 1. Introduction Davis, S.D. Emerging Genotype- Phenotype Relationships in Primary Motile ciliopathies are a group of disorders where motile cilia lining embryonic cells, Ciliary Dyskinesia. Int. J. Mol. Sci. airways, sinus and inner ear cavities, and ventricles in the brain are dysfunctional. The 2021, 22, 8272. https://doi.org/ primary function of these hair-like projections is to facilitate the movement of fluid (i.e., 10.3390/ijms22158272 mucus that lines the airways, cerebrospinal fluid) within various body cavities to be either recirculated or expelled [1]. Research into the structure and function of cilia in the last Academic Editors: Michał P. Witt, two decades has provided insights into the complex arrangement of the individual cilia Ewa Zi˛etkiewiczand Zuzanna components, and how genetic variation impacts component assembly and subsequent cilia Bukowy-Bieryłło function. This review will provide an overview of cilia structure and function, the genes involved in cilia assembly, and the phenotypic consequences of genetic variants in primary Received: 1 July 2021 ciliary dyskinesia (PCD). Accepted: 26 July 2021 Published: 31 July 2021 2. Overview of Primary Ciliary Dyskinesia Presenting frequently in an autosomal recessive manner, PCD is a rare inherited Publisher’s Note: MDPI stays neutral disorder of motile cilia with an estimated incidence of 1:10,000 to 1:20,000 [2]. The condition with regard to jurisdictional claims in typically presents early in life, with many infants experiencing respiratory distress at birth published maps and institutional affil- despite being born at term [3]. Symptoms of PCD are directly related to ineffective or absent iations. beating of motile cilia in the embryonic node, respiratory, reproductive, and neurologic systems. This dysfunction results in impaired mucus clearance in the airways, abnormal sperm movement, or altered fluid flow in the fallopian tubes and ventricles within the brain. Affected people can present with a variable phenotype that can be severe or mild, leading Copyright: © 2021 by the authors. to diagnostic challenges. Symptoms include chronic daily wet cough, chronic rhinorrhea, Licensee MDPI, Basel, Switzerland. recurrent sinusitis, recurrent otitis media, bronchiectasis, infertility (or subfertility), situs This article is an open access article abnormalities, and rarely hydrocephalus [4]. Sino-pulmonary symptoms are typically distributed under the terms and the most common manifestations of the condition. Approximately fifty percent of people conditions of the Creative Commons with PCD will present with situs inversus, and heterotaxy is more common in this disease. Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ Practitioners who see people with these complaints should have a high degree of suspicion 4.0/). for PCD so early identification and diagnostic testing can be performed. Int. J. Mol. Sci. 2021, 22, 8272. https://doi.org/10.3390/ijms22158272 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 15 PCD will present with situs inversus, and heterotaxy is more common in this disease. Prac- titioners who see people with these complaints should have a high degree of suspicion for Int. J. Mol. Sci. 2021, 22, 8272 PCD so early identification and diagnostic testing can be performed. 2 of 15 3. Cilia Structure and Function 3. Cilia Structure3.1. and Overview Function 3.1. Overview Cilia are organized structures of microtubules which protrude from the cell surface, Cilia are organizedserving many structures physiologic of microtubules functions. Cilia which are protrude grouped from into categories the cell surface, as motile or non-mo- serving many physiologictile, and can functions.have either Cilia a 9+2 are or 9+0 grouped arrangement into categories of microtubule as motile doublets or non- (Figure 1) [1]. motile, and can have either a 9+2 or 9+0 arrangement of microtubule doublets (Figure1) [1]. Figure 1. Diagram of basic cilia structure in 9+2 and 9+0 microtubule arrangements. MotileFigure cilia 1. Diagram possessing of basic the cilia 9+2 structure arrangement in 9+2 and are 9+0 found microtubule primarily arrangements. in the upper and lower respiratory tract, female reproductive tract, and spermatozoan. The primary function of motile cilia with theMotile 9+2 cilia arrangement possessing is tothe move 9+2 arrangement liquid and/or are mucous found parallel primarily to thein the upper and cells’ surface orlower in the respiratory case of spermatozoan tract, female flagellum, reproductive these tract, cilia and lead spermatozoan. to the propulsion The primary func- of the sperm. Motiletion of ciliamotile possessing cilia with thethe 9+09+2 arrangement is are tofound move inliquid the embryonicand/or mucous parallel to node and play athe primary cells’ surface role in determiningor in the case left-right of spermatozoan asymmetry flagellum, of organs these during cilia human lead to the propul- development bysion directing of the sperm. fluid flow Motile across cilia the possessing cell surface the [ 59+0]. This arrangement is achieved are through found in a the embryonic rotational motionnode of and the cilium,play a primary which contrasts role in determining to the “wave-like” left-right motion asymmetry of the motileof organs during hu- 9+2 cilia. Finally,man primary development cilia are usuallyby directing solitary, fluid nonmotile flow across organelles the cell that surface typically [5]. have This is achieved a “9+0” microtubulethrough configuration. a rotational Present motion on of the the surface cilium, of which most non-dividingcontrasts to the cells, “wave-like” these motion of structures sensethe the motile extracellular 9+2 cilia. environment. Finally, primary Additionally, cilia are theyusually regulate solitary, developmental nonmotile organelles that pathways, andtypically defects lead have to a a “9+0” growing microtubule number of configuration. complex clinically Present varied on the conditions. surface of most non-di- Affected individualsviding can cells, have these diverse structures features, sense such the as extr variableacellular mental environment. disabilities, Additionally, skeletal they reg- anomalies, obesity,ulate retinal developmental degeneration, pathways, and polycystic and defects kidneys lead to [6 a]. growing While overlapping number of complex clini- conditions havecally been varied described, conditions. the role Affected of these individuals structures is ca notn have in fluid diverse movement features, and such as variable thus are not directlymental implicated disabilities, in theskeletal pathogenesis anomalies, of motileobesity, ciliopathies retinal degeneration, [7]. and polycystic kid- neys [6]. While overlapping conditions have been described, the role of these structures is 3.2. Respiratory Cilia not in fluid movement and thus are not directly implicated in the pathogenesis of motile Cilia liningciliopathies the upper and[7]. lower respiratory tracts have a 9+2 configuration of micro- tubules that extend from the apical cell surface. Hundreds of these cilia are present on each ciliated cell3.2. and Respiratory they move Cilia in a coordinated fashion, leading to effective mucociliary clearance or movement of mucus from the lower to the upper respiratory tract, out of the Cilia lining the upper and lower respiratory tracts have a 9+2 configuration of micro- sinus ostia, or out of the middle ear space. The cilia structure is stabilized by hundreds of tubules that extend from the apical cell surface. Hundreds of these cilia are present on proteins whose alteration can produce the phenotype seen in PCD. A normally structured each ciliated cell and they move in a coordinated fashion, leading to effective mucociliary cilium shows an arrangement of nine microtubule doublets that are arranged along the clearance or movement of mucus from the lower to the upper respiratory tract, out of the circumference of the cilia along with another pair in the center referred to as the central sinus ostia, or out of the middle ear space. The cilia structure is stabilized by hundreds of apparatus or central complex. The outer doublets are anchored to the central complex by proteins whose alteration can produce the phenotype
Load more

Recommended publications
  • 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
    [Show full text]
  • 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.
    [Show full text]
  • Bayesian Hierarchical Modeling of High-Throughput Genomic Data with Applications to Cancer Bioinformatics and Stem Cell Differentiation
    BAYESIAN HIERARCHICAL MODELING OF HIGH-THROUGHPUT GENOMIC DATA WITH APPLICATIONS TO CANCER BIOINFORMATICS AND STEM CELL DIFFERENTIATION by Keegan D. Korthauer A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Statistics) at the UNIVERSITY OF WISCONSIN–MADISON 2015 Date of final oral examination: 05/04/15 The dissertation is approved by the following members of the Final Oral Committee: Christina Kendziorski, Professor, Biostatistics and Medical Informatics Michael A. Newton, Professor, Statistics Sunduz Kele¸s,Professor, Biostatistics and Medical Informatics Sijian Wang, Associate Professor, Biostatistics and Medical Informatics Michael N. Gould, Professor, Oncology © Copyright by Keegan D. Korthauer 2015 All Rights Reserved i in memory of my grandparents Ma and Pa FL Grandma and John ii ACKNOWLEDGMENTS First and foremost, I am deeply grateful to my thesis advisor Christina Kendziorski for her invaluable advice, enthusiastic support, and unending patience throughout my time at UW-Madison. She has provided sound wisdom on everything from methodological principles to the intricacies of academic research. I especially appreciate that she has always encouraged me to eke out my own path and I attribute a great deal of credit to her for the successes I have achieved thus far. I also owe special thanks to my committee member Professor Michael Newton, who guided me through one of my first collaborative research experiences and has continued to provide key advice on my thesis research. I am also indebted to the other members of my thesis committee, Professor Sunduz Kele¸s,Professor Sijian Wang, and Professor Michael Gould, whose valuable comments, questions, and suggestions have greatly improved this dissertation.
    [Show full text]
  • 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.
    [Show full text]
  • Accuracy of Immunofluorescence in the Diagnosis of Primary Ciliary Dyskinesia
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UCL Discovery Accuracy of immunofluorescence in the diagnosis of Primary Ciliary Dyskinesia Amelia Shoemark1,2, Emily Frost 1, Mellisa Dixon 1, Sarah Ollosson 1, Kate Kilpin1, Andrew V Rogers 1 , Hannah M Mitchison3, Andrew Bush1,2, Claire Hogg1 1 Department of Paediatrics, Royal Brompton & Harefield NHS Trust, London, UK 2 National Heart and Lung Institute, Imperial College London, UK 3 Genetics and Genomic Medicine Programme, Institute of Child Health, University College London, UK Correspondence to: Amelia Shoemark Primary Ciliary Dyskinesia Service Electron microscopy unit Department of Paediatrics Royal Brompton Hospital London SW3 6NP Statement of contribution: AS, CH and AB designed the study. EF, KK, SO and AS consented patients, conducted light microscopy, collected nasal brushings and prepared slides. EF and AS conducted IF staining and analysis. MD conducted light and electron microscopy. HM provided genotyping. AS and EF analysed the data. AS, CH and AB drafted the manuscript. All authors contributed to manuscript drafts and preparation. AS is custodian of the data and takes responsibility for its accuracy. Sources of support: This project is funded by a NIHR fellowship awarded to AS and mentored by CH, HM and AB. AB was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London Running head: Immunofluorescence in PCD diagnosis Descriptor number:14.6 Rare paediatric lung disease Word count (excluding abstract and references): 2872 At a Glance Commentary: Scientific Knowledge on the Subject Primary Ciliary Dyskinesia is a genetically heterogeneous chronic condition.
    [Show full text]
  • RSPH3 (NM 031924) Human Recombinant Protein – TP761392
    OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TP761392 RSPH3 (NM_031924) Human Recombinant Protein Product data: Product Type: Recombinant Proteins Description: Purified recombinant protein of Human radial spoke 3 homolog (Chlamydomonas) (RSPH3), full length, with N-terminal GST and C-terminal HIS tag, expressed in E. coli, 50ug Species: Human Expression Host: E. coli Tag: N-GST and C-His Predicted MW: 91.5 kDa Concentration: >50 ug/mL as determined by microplate BCA method Purity: > 80% as determined by SDS-PAGE and Coomassie blue staining Buffer: 25mM Tris,pH8.0,150mM NaCl,10% glycerol,1% Sarkosyl. Storage: Store at -80°C. Stability: Stable for 12 months from the date of receipt of the product under proper storage and handling conditions. Avoid repeated freeze-thaw cycles. RefSeq: NP_114130 Locus ID: 83861 UniProt ID: Q86UC2 RefSeq Size: 2201 Cytogenetics: 6q25.3 RefSeq ORF: 1680 Synonyms: CILD32; dJ111C20.1; RSHL2; RSP3 Summary: The protein encoded by this gene acts as a protein kinase A anchoring protein. Mutations in this gene cause primary ciliary dyskinesia; a disorder characterized by defects of the axoneme in motile cilia and sperm flagella. The homolog of this gene was first identified in the blue- green algae Chlamydomonas as encoding a radial spoke protein that formed a structural component of motile cilia and flagella. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016] This product is to be used for laboratory only.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [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]
  • Utilization of Genomic Sequencing for Population Screening of Immunodeficiencies in the Newborn
    © American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Utilization of genomic sequencing for population screening of immunodeficiencies in the newborn Ashleigh R. Pavey, MD1,2,3, Dale L. Bodian, PhD3, Thierry Vilboux, PhD3, Alina Khromykh, MD3, Natalie S. Hauser, MD3,4, Kathi Huddleston, PhD3, Elisabeth Klein, DNP3, Aaron Black, MS3, Megan S. Kane, PhD3, Ramaswamy K. Iyer, PhD3, John E. Niederhuber, MD3,5 and Benjamin D. Solomon, MD3,4,6 Purpose: Immunodeficiency screening has been added to many Results: WGS provides adequate coverage for most known state-directed newborn screening programs. The current metho- immunodeficiency-related genes. 13,476 distinct variants and dology is limited to screening for severe T-cell lymphopenia 8,502 distinct predicted protein-impacting variants were identified disorders. We evaluated the potential of genomic sequencing to in this cohort; five individuals carried potentially pathogenic augment current newborn screening for immunodeficiency, – variants requiring expert clinical correlation. One clinically including identification of non T cell disorders. asymptomatic individual was found genomically to have comple- Methods: We analyzed whole-genome sequencing (WGS) and ment component 9 deficiency. Of the symptomatic children, one clinical data from a cohort of 1,349 newborn–parent trios by was molecularly identified as having an immunodeficiency condi- genotype-first and phenotype-first approaches. For the genotype- tion and two were found to have other molecular diagnoses. first approach, we analyzed predicted protein-impacting variants in Conclusion: Neonatal genomic sequencing can potentially aug- 329 immunodeficiency-related genes in the WGS data. As a ment newborn screening for immunodeficiency. phenotype-first approach, electronic health records were used to identify children with clinical features suggestive of immunodefi- Genet Med advance online publication 15 June 2017 ciency.
    [Show full text]
  • 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.
    [Show full text]
  • Reconstructions of Centriole Formation and Ciliogenesis in Mammalian Lungs
    J. Cell Sci. 3, 207-230 (1968) 207 Printed in Great Britain RECONSTRUCTIONS OF CENTRIOLE FORMATION AND CILIOGENESIS IN MAMMALIAN LUNGS S. P. SOROKIN Department of Anatomy, Harvard Medical School, Boston, Massachusetts 02115, U.S.A. SUMMARY This study presents reconstructions of the processes of centriolar formation and ciliogenesis based on evidence found in electron micrographs of tissues and organ cultures obtained chiefly from the lungs of foetal rats. A few observations on living cultures supplement the major findings. In this material, centrioles are generated by two pathways. Those centrioles that are destined to participate in forming the achromatic figure, or to sprout transitory, rudimentary (primary) cilia, arise directly off the walls of pre-existing centrioles. In pulmonary cells of all types this direct pathway operates during interphase. The daughter centrioles are first recognizable as annular structures (procentrioles) which lengthen into cylinders through acropetal deposition of osmiophilic material in the procentriolar walls. Triplet fibres develop in these walls from singlet and doublet fibres that first appear near the procentriolar bases and thereafter extend apically. When little more than half grown, the daughter centrioles are released into the cyto- plasm, where they complete their maturation. A parent centriole usually produces one daughter at a time. Exceptionally, up to 8 have been observed to develop simultaneously about 1 parent centriole. Primary cilia arise from directly produced centrioles in differentiating pulmonary cells of all types throughout the foetal period. In the bronchial epithelium they appear before the time when the ciliated border is generated. Fairly late in foetal life, centrioles destined to become kinetosomes in ciliated cells of the epithelium become assembled from masses of fibrogranular material located in the apical cytoplasm.
    [Show full text]
  • Role of Non-Motile Microtubule-Associated Proteins in Virus Trafficking
    BioMol Concepts 2016; 7(5-6): 283–292 Review Débora M. Portilho, Roger Persson and Nathalie Arhel* Role of non-motile microtubule-associated proteins in virus trafficking DOI 10.1515/bmc-2016-0018 continuously switching between phases of growth and Received June 21, 2016; accepted November 4, 2016 shrinkage, referred to as dynamic instability (1). MTs are involved in a wide range of cellular functions, including Abstract: Viruses are entirely dependent on their ability cell morphology, division, motility, and organelle posi- to infect a host cell in order to replicate. To reach their site tioning, as well as in disease, such as neurodegenerative of replication as rapidly and efficiently as possible follow- disease, infection and immunity. Once the MT filaments ing cell entry, many have evolved elaborate mechanisms are formed by nucleation at the centrosome and elon- to hijack the cellular transport machinery to propel them- gated from the subunit pool, their stability and mechani- selves across the cytoplasm. Long-range movements have cal properties are often controlled by a set of proteins that been shown to involve motor proteins along microtubules bind along the polymer. These so-called microtubule- (MTs) and direct interactions between viral proteins and associated proteins (MAPs, not to be confused with mito- dynein and/or kinesin motors have been well described. gen-activated proteins) are essential for the regulation of Although less well-characterized, it is also becoming MT dynamics. increasingly clear that non-motile microtubule-associated Several types of MAPs have been identified in eukary- proteins (MAPs), including structural MAPs of the MAP1 otes, including MT motors, MT plus-end and minus-end and MAP2 families, and microtubule plus-end tracking tracking proteins (+ TIPs, − TIPs), centrosome-associated proteins (+ TIPs), can also promote viral trafficking in proteins and structural MAPs.
    [Show full text]