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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. -
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). -
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. -
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. -
NME8 Rs2718058 Polymorphism with Alzheimer's Disease Risk
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 24 Research Paper NME8 rs2718058 polymorphism with Alzheimer’s disease risk: a replication and meta-analysis Shu-Lei Liu1, Xue-Chun Wang2, Meng-Shan Tan1, Hui-Fu Wang1, Wei Zhang1, Zi-Xuan Wang1, Jin-Tai Yu1, Lan Tan1 1Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, PR China 2Department of Radiology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, PR China Correspondence to: Lan Tan, email: [email protected] Jin-Tai Yu, email: [email protected] Keywords: NME8, Alzheimer’s disease, association study, polymorphism, meta-analysis Received: March 01, 2016 Accepted: April 11, 2016 Published: April 28, 2016 ABSTRACT Recently, a large meta-analysis of five genome wide association studies (GWAS) has identified that a novel single nucleotide polymorphism (SNP) rs2718058, adjacent to gene NME8 on chromosome 7p14.1, was associated with late-onset Alzheimer’s disease (LOAD) in Caucasians. However, the effect of rs2718058 on other populations remains unclear. In order to explore the relationship between rs2718058 and LOAD risk in a North Han Chinese population, we recruited 984 LOAD cases and 1354 healthy controls that matched for sex and age in this study. The results showed no significant differences in the genotypic or allelic distributions of rs2718058 polymorphism between LOAD cases and healthy controls, even though after stratification forAPOE ε4 status and statistical adjustment for age, gender and APOE ε4 status (p > 0.05). However, a meta-analysis conducted in a sample of 82513 individuals confirmed a significant association between SNP rs2718058 and LOAD risk (OR = 1.08, 95%CI = 1.05–1.11) in the whole population. -
Joubert Syndrome Genereview
Title: Joubert Syndrome GeneReview — Molecular Genetics: Less Common Genetic Causes Authors: Parisi M, Glass I Updated: June 2017 Note: The following information is provided by the authors listed above and has not been reviewed by GeneReviews staff. Joubert Syndrome: Less Common Genetic Causes ARL13B B9D1 B9D2 CEP41 IFT172 KIF7 OFD1 (CXORF5) PDE6D POC1B TCTN1 TCTN3 TMEM138 TMEM231 TMEM237 (ALS2CR4) TTC21B ARL13B Gene structure. ARL13B is a ten-exon gene that encodes a 428-amino acid protein. Pathogenic variants. Two families with a phenotype typical of classic Joubert syndrome had missense and/or nonsense variants in this gene; one of these individuals also had evidence of a retinopathy [Cantagrel et al 2008]. Normal gene product. ARL13B encodes ADP-ribosylation factor-like protein 13B, a member of the ADP-ribosylation factor-like family. Multiple transcript variants result from alternate splicing; two protein isoforms are known. The AR13B protein is a small GTPase in the Ras superfamily that contains both N-terminal and C-terminal guanine nucleotide-binding motifs. It is localized to the cilia and plays a role in cilia formation and maintenance as well as sonic hedgehog signaling. Abnormal gene product. In C elegans, pathogenic variants in the homolog arl13 exhibit defective cilium morphology, localization, and anterograde intraflagellar transport [Cevik et al 2010]. Mice with defects in the murine ortholog have neural tube defects and polydactyly, as well as an embryonic-lethal phenotype [Cantagrel et al 2008, Doherty 2009]. B9D1. See Tables A and B. B9D2. See Tables A and B. CEP41 Gene structure. The gene consists of 11 exons and spans approximately 50 kb. -
Transmission Distortion and Genetic Incompatibilities Between Alleles in A
bioRxiv preprint doi: https://doi.org/10.1101/2021.06.09.447720; this version posted June 10, 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-NC-ND 4.0 International license. 1 Transmission distortion and genetic incompatibilities between alleles in a 2 multigenerational mouse advanced intercross line 3 Danny Arends, [email protected], Albrecht Daniel Thaer-Institut für Agrar- und 4 Gartenbauwissenschaften, Humboldt-Universität zu Berlin, Invalidenstraße 42, D-10115 Berlin, 5 Germany 6 Stefan Kärst, [email protected], Albrecht Daniel Thaer-Institut für Agrar- und 7 Gartenbauwissenschaften, Humboldt-Universität zu Berlin, Invalidenstraße 42, D-10115 Berlin, 8 Germany 9 Sebastian Heise, [email protected], Albrecht Daniel Thaer-Institut für Agrar- und 10 Gartenbauwissenschaften, Humboldt-Universität zu Berlin, Invalidenstraße 42, D-10115 Berlin, 11 Germany 12 Paula Korkuc, [email protected], Albrecht Daniel Thaer-Institut für Agrar- und 13 Gartenbauwissenschaften, Humboldt-Universität zu Berlin, Invalidenstraße 42, D-10115 Berlin, 14 Germany 15 Deike Hesse, [email protected], Albrecht Daniel Thaer-Institut für Agrar- und 16 Gartenbauwissenschaften, Humboldt-Universität zu Berlin, Invalidenstraße 42, D-10115 Berlin, 17 Germany 18 Gudrun A. Brockmann†, [email protected], Albrecht Daniel Thaer-Institut für Agrar- 19 und Gartenbauwissenschaften, Humboldt-Universität zu Berlin, Invalidenstraße 42, D-10115 Berlin, 20 Germany 21 † To whom correspondence should be addressed. 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.09.447720; this version posted June 10, 2021. -
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. -
Dysregulation of Sonic Hedgehog Signaling
RESEARCH ARTICLE Dysregulation of sonic hedgehog signaling causes hearing loss in ciliopathy mouse models Kyeong-Hye Moon1,2, Ji-Hyun Ma1, Hyehyun Min1, Heiyeun Koo1,2, HongKyung Kim1, Hyuk Wan Ko3*, Jinwoong Bok1,2,4* 1Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea; 2BK21 PLUS project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea; 4Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea Abstract Defective primary cilia cause a range of diseases known as ciliopathies, including hearing loss. The etiology of hearing loss in ciliopathies, however, remains unclear. We analyzed cochleae from three ciliopathy mouse models exhibiting different ciliogenesis defects: Intraflagellar transport 88 (Ift88), Tbc1d32 (a.k.a. bromi), and Cilk1 (a.k.a. Ick) mutants. These mutants showed multiple developmental defects including shortened cochlear duct and abnormal apical patterning of the organ of Corti. Although ciliogenic defects in cochlear hair cells such as misalignment of the kinocilium are often associated with the planar cell polarity pathway, our results showed that inner ear defects in these mutants are primarily due to loss of sonic hedgehog signaling. Furthermore, an inner ear-specific deletion of Cilk1 elicits low-frequency hearing loss attributable to cellular changes in apical cochlear identity that is dedicated to low-frequency sound detection. This type of hearing loss may account for hearing deficits in some patients with ciliopathies. *For correspondence: [email protected] (HWK); [email protected] (JB) Competing interests: The Introduction authors declare that no The primary cilium is a microtubule-based organelle protruding from the apical surface of nearly all competing interests exist. -
Novel Gene Discovery in Primary Ciliary Dyskinesia
Novel Gene Discovery in Primary Ciliary Dyskinesia Mahmoud Raafat Fassad Genetics and Genomic Medicine Programme Great Ormond Street Institute of Child Health University College London A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy University College London 1 Declaration I, Mahmoud Raafat Fassad, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Primary Ciliary Dyskinesia (PCD) is one of the ‘ciliopathies’, genetic disorders affecting either cilia structure or function. PCD is a rare recessive disease caused by defective motile cilia. Affected individuals manifest with neonatal respiratory distress, chronic wet cough, upper respiratory tract problems, progressive lung disease resulting in bronchiectasis, laterality problems including heart defects and adult infertility. Early diagnosis and management are essential for better respiratory disease prognosis. PCD is a highly genetically heterogeneous disorder with causal mutations identified in 36 genes that account for the disease in about 70% of PCD cases, suggesting that additional genes remain to be discovered. Targeted next generation sequencing was used for genetic screening of a cohort of patients with confirmed or suggestive PCD diagnosis. The use of multi-gene panel sequencing yielded a high diagnostic output (> 70%) with mutations identified in known PCD genes. Over half of these mutations were novel alleles, expanding the mutation spectrum in PCD genes. The inclusion of patients from various ethnic backgrounds revealed a striking impact of ethnicity on the composition of disease alleles uncovering a significant genetic stratification of PCD in different populations. -
Lab Respiratory NGS Requisition Form
4305 Oakes Road STE 513 Davie, Florida 33314 954-541-3705 www.asaplab.com Respiratory Infection Requisition CLIA# 10D2079014: Lab Director: Dr. Kambiz Yaraei, PhD FACILITY DEMOGRAPHICS PATIENT DEMOGRAPHICS Name: Name: Male Female Address: Phone: DOB: City: State: Zip: Address: Phone: City: State: Zip: Specimen Collection Ancestry (Circle): Date of Collection: Caucasian Eastern European Northern European Time of Collection: Western European Native American Middle Eastern African American Asian Pacific Islander Notes: Caribbean Central / South Other ______ Ashkenazi Jewish American Hispanic Physician Name: NPI: BILLING INFORMATION Bill: (Circle) Insurance HAS Medicaid Medicare Self Pay Workers Compensation Name of Policy Holder: Medicare # Medicaid # Relationship to Policy Holder (Circle) Worker’s Comp Claim # Date of Injury Self Spouse Dependent Other: _____________ Policy # Group # Insurance Company: PATIENT CONSENT MEDICAL NECESSITY Billing ABN and Patient Plan Information: A completed Advance Beneficiary This test is medically necessary for the diagnosis or detection of a disease, Notice (ABN) of coverage is required for Medicare patients who do not meet illness, impairment, syndrome or disorder, and these results will be used in the medical criteria for testing. This does not apply to specific site analyses. medical management and treatment for this patient. Furthermore, recipients’ Insurance pre-qualification will not be performed for these tests, unless information is true and correct to the best of my knowledge. specifically requested. All tests ordered shall be processed and billed based on The person listed as the Ordering Physician or genetic counselor is authorized by payor. law to order the test(s) requested herein. I confirm that I have provided genetic Patient Acknowledgment: I am covered by insurance and authorize ASAP testing information to the patient and they have consented to genetic testing. -
Microrna-124-3P Suppresses Mouse Lip Mesenchymal Cell Proliferation
Suzuki et al. BMC Genomics (2019) 20:852 https://doi.org/10.1186/s12864-019-6238-4 RESEARCH ARTICLE Open Access MicroRNA-124-3p suppresses mouse lip mesenchymal cell proliferation through the regulation of genes associated with cleft lip in the mouse Akiko Suzuki1,2, Hiroki Yoshioka1,2, Dima Summakia1, Neha G. Desai1,3, Goo Jun3,4, Peilin Jia5, David S. Loose4,6, Kenichi Ogata1,2, Mona V. Gajera1,3, Zhongming Zhao3,4,5 and Junichi Iwata1,2,4* Abstract Background: Cleft lip (CL), one of the most common congenital birth defects, shows considerable geographic and ethnic variation, with contribution of both genetic and environmental factors. Mouse genetic studies have identified several CL-associated genes. However, it remains elusive how these CL-associated genes are regulated and involved in CL. Environmental factors may regulate these genes at the post-transcriptional level through the regulation of non-coding microRNAs (miRNAs). In this study, we sought to identify miRNAs associated with CL in mice. Results: Through a systematic literature review and a Mouse Genome Informatics (MGI) database search, we identified 55 genes that were associated with CL in mice. Subsequent bioinformatic analysis of these genes predicted that a total of 33 miRNAs target multiple CL-associated genes, with 20 CL-associated genes being potentially regulated by multiple miRNAs. To experimentally validate miRNA function in cell proliferation, we conducted cell proliferation/viability assays for the selected five candidate miRNAs (miR-124-3p, let-7a-5p, let-7b-5p, let-7c-5p, and let-7d-5p). Overexpression of miR-124-3p, but not of the others, inhibited cell proliferation through suppression of CL-associated genes in cultured mouse embryonic lip mesenchymal cells (MELM cells) isolated from the developing mouse lip region.