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Ciliopathies About Emory Genetics Laboratory (EGL) EGL specializes in genetic diagnostic testing, with 45 years of clinical experience and board-certified laboratory directors and genetic counselors reporting out cases. EGL offers a combined 1100 molecular genetics, biochemical genetics, and cytogenetics tests under one roof and custom testing for all medically relevant genes, for domestic and international clients. Equally important to improving patient care through quality genetic testing is the contribution EGL makes back to the scientific and medical communities. EGL is one of only a few clinical diagnostic laboratories to openly share data with the NCBI freely available public database ClinVar (>7000 variants on >500 genes) and is also the only laboratory with a free online database (EmVClass), featuring a variant classification search and report request interface, which facilitates rapid interactive curation and reporting of variants. Ciliopathies Panel The ciliopathies are a group of disorders caused by mutation in genes that encode proteins involved in the formation and function of cilia. Cilia are microtubule-based, hair-like cytoplasmic extensions from the cell surface and are found on almost all cell types. They play a part in multiple biological processes, including cellular motility, extracellular fluid movement, and sensory and signal transduction pathways. As many developmental and physiological functions are dependent on cilia, defects in cilia may lead to disorders in many different organ systems and processes, including: • renal disease • cerebral anomalies • congenital fibrocystic diseases • retinal degeneration • skeletal dysplasia of the pancreas and liver • diabetes • obesity There are 112 genes on the Ciliopathies Panel (please see reverse side for a list of genes analyzed). The panel tests for genes involved in numerous ciliopathy disorders, including: • primary ciliary dyskinesia • Senior-Loken syndrome • Bardet-Biedl syndrome • heterotaxy • Leber congenital amaurosis • Meckel-Gruber syndrome • Joubert and related syndromes • Usher syndrome • nephronophthisis EGL offers the Ciliopathies Panel to aid in diagnosis when a ciliopathy is suspected. Ordering the Ciliopathies Panel can be more cost-effective than single-gene analysis when the specific gene involved in a patient’s disorder is not readily apparent. References: 1. Ferkol and Leigh, (2011), J Pediatr, 160:366-371. 2. Hildebrandt et al., (2011), New Engl J Med, 364:1533-1543. 3. Ware et al., (2011), Proc Am Thorac Soc, 8:444-450. 4. Waters and Beales, (2011), Pediatr Nephrol, 26:1039-1056. Ciliopathies Genes Included on the Ciliopathies Panel* ACVR2B BBS12 CRX GLIS2 MKS1 RDH12 TMEM138 VHL AHI1 C2orf71 DFNB31 GPR98 MYO7A RPE65 TMEM216 WDPCP AIPL1 C5orf42 DNAAF1 GUCY2D NEK1 RPGR TMEM231 WDR19 ARL13B CC2D2A DNAAF2 HYLS1 NEK8 RPGRIP1 TMEM237 WDR35 ARL6 CCDC28B DNAAF3 IFT43 NKX2-5 RPGRIP1L TOPORS XPNPEP3 ATXN10 CCDC39 DNAH5 IFT80 NME8 RSPH4A TRIM32 ZIC3 B9D1 CCDC40 DNAH11 IMPDH1 NODAL RSPH9 TSC1 ZNF423 B9D2 CDH23 DNAI1 INVS NPHP1 SCNN1A TSC2 BBS1 CEP164 DNAI2 IQCB1 NPHP3 SCNN1B TTC21B BBS2 CEP290 DNAL1 KCNJ13 NPHP4 SCNN1G TTC8 BBS4 CEP41 DYNC2H1 KIF7 OFD1 SDCCAG8 TULP1 BBS5 CFTR EVC LCA5 PCDH15 SPATA7 UMOD BBS7 CLRN1 EVC2 LEFTY2 PKD2 TCTN1 USH1C BBS9 CRB1 FOXH1 LRAT PKHD1 TCTN2 USH1G BBS10 CRELD1 GDF1 MKKS RD3 TMEM67 USH2A *Please note that deletion/duplication analysis is not completed for all genes in the panel. Some genes on this panel are associated with additional phenotypes. All genes on the next generation sequencing panel may be ordered separately. Genes included on panels are subject to change. Why Choose EGL? • The EGL Ciliopathies Panel is the most comprehensive ciliopathies panel available. • Free parental testing for up to two changes identified on the panel • Guaranteed 100% coverage with Sanger sequencing fill-in for low coverage regions Test Code Test Name CPT®** Codes MCIL1 Ciliopathies: Sequencing Panel 81404 (x1), 81405 (x1), 81406 (x1) DCIL1 Ciliopathies: Deletion/Duplication Panel 81403 (x1), 81405 (x1), 81406 (x1) **CPT® is a registered trademark of the American Medical Association. For more information about EGL and the nearly 1100 tests we offer: EMAIL CALL WEB [email protected] 404-778-8499 www.geneticslab.emory.edu.
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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
  • Near-Atomic Structures of the Bbsome Reveal the Basis for Bbsome

    Near-Atomic Structures of the Bbsome Reveal the Basis for Bbsome

    RESEARCH ARTICLE Near-atomic structures of the BBSome reveal the basis for BBSome activation and binding to GPCR cargoes Shuang Yang1†, Kriti Bahl2†, Hui-Ting Chou1‡, Jonathan Woodsmith3, Ulrich Stelzl3, Thomas Walz1*, Maxence V Nachury2* 1Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, United States; 2Department of Ophthalmology, University of California San Francisco, San Francisco, United States; 3Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, University of Graz and BioTechMed-Graz, Graz, Austria Abstract Dynamic trafficking of G protein-coupled receptors (GPCRs) out of cilia is mediated by the BBSome. In concert with its membrane recruitment factor, the small GTPase ARL6/BBS3, the BBSome ferries GPCRs across the transition zone, a diffusion barrier at the base of cilia. Here, we present the near-atomic structures of the BBSome by itself and in complex with ARL6GTP, and we describe the changes in BBSome conformation induced by ARL6GTP binding. Modeling the *For correspondence: interactions of the BBSome with membranes and the GPCR Smoothened (SMO) reveals that SMO, [email protected] (TW); and likely also other GPCR cargoes, must release their amphipathic helix 8 from the membrane to [email protected] (MVN) be recognized by the BBSome. †These authors contributed equally to this work Present address: ‡Department of Therapeutic Discovery, Amgen Introduction Inc, South San Francisco, United Cilia dynamically concentrate signaling receptors to sense and transduce signals as varied as light, States odorant molecules, Hedgehog morphogens and ligands of G protein-coupled receptors (GPCRs) Competing interests: The (Anvarian et al., 2019; Bangs and Anderson, 2017; Nachury and Mick, 2019). Highlighting the authors declare that no functional importance of dynamic ciliary trafficking, the appropriate transduction of Hedgehog signal competing interests exist.
  • Ciliopathiesneuromuscularciliopathies Disorders Disorders Ciliopathiesciliopathies

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    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.
  • Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity Received: 11 November 2016 Audrey E

    Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity Received: 11 November 2016 Audrey E

    www.nature.com/scientificreports OPEN Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity Received: 11 November 2016 Audrey E. Hendricks1,2, Elena G. Bochukova3,4, Gaëlle Marenne1, Julia M. Keogh3, Neli Accepted: 10 April 2017 Atanassova3, Rebecca Bounds3, Eleanor Wheeler1, Vanisha Mistry3, Elana Henning3, Published: xx xx xxxx Understanding Society Scientific Group*, Antje Körner5,6, Dawn Muddyman1, Shane McCarthy1, Anke Hinney7, Johannes Hebebrand7, Robert A. Scott8, Claudia Langenberg8, Nick J. Wareham8, Praveen Surendran9, Joanna M. Howson9, Adam S. Butterworth9,10, John Danesh1,9,10, EPIC-CVD Consortium*, Børge G Nordestgaard11,12, Sune F Nielsen11,12, Shoaib Afzal11,12, SofiaPa padia3, SofieAshford 3, Sumedha Garg3, Glenn L. Millhauser13, Rafael I. Palomino13, Alexandra Kwasniewska3, Ioanna Tachmazidou1, Stephen O’Rahilly3, Eleftheria Zeggini1, UK10K Consortium*, Inês Barroso1,3 & I. Sadaf Farooqi3 Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants inBBS1 , BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10−3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes.
  • TRIM32 Is an E3 Ubiquitin Ligase for Dysbindin

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    Human Molecular Genetics, 2009, Vol. 18, No. 13 2344–2358 doi:10.1093/hmg/ddp167 Advance Access published on April 6, 2009 TRIM32 is an E3 ubiquitin ligase for dysbindin Matthew Locke1,2, Caroline L. Tinsley1, Matthew A. Benson2,{ and Derek J. Blake1,Ã 1Department of Psychological Medicine, Cardiff University, Henry Wellcome Building for Biomedical Research in Wales, Heath Park, Cardiff, CF14 4XN, UK and 2Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK Received December 15, 2008; Revised and Accepted April 2, 2009 Mutations in the gene encoding tripartite motif protein 32 (TRIM32) cause two seemingly diverse diseases: limb-girdle muscular dystrophy type 2H (LGMD2H) or sarcotubular myopathy (STM) and Bardet–Biedl syndrome type 11(BBS11). Although TRIM32 is involved in protein ubiquitination, its substrates and the molecular consequences of disease-causing mutations are poorly understood. In this paper, we show that Downloaded from TRIM32 is a widely expressed ubiquitin ligase that is localized to the Z-line in skeletal muscle. Using the yeast two-hybrid system, we found that TRIM32 binds and ubiquitinates dysbindin, a protein implicated in the genetic aetiology of schizophrenia, augmenting its degradation. Small-interfering RNA-mediated knock-down of TRIM32 in myoblasts resulted in elevated levels of dysbindin. Importantly, the LGMD2H/ STM-associated TRIM32 mutations, D487N and R394H impair ubiquitin ligase activity towards dysbindin http://hmg.oxfordjournals.org/ and were mislocalized in heterologous cells. These mutants were able to self-associate and also co-immuno- precipitated with wild-type TRIM32 in transfected cells. Furthermore, the D487N mutant could bind to both dysbindin and its E2 enzyme but was defective in monoubiquitination.
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  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

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  • European School of Genetic Medicine Eye Genetics

    European School of Genetic Medicine Eye Genetics

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  • Ciliopathies Gene Panel

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  • De Novo, Systemic, Deleterious Amino Acid Substitutions Are Common in Large Cytoskeleton‑Related Protein Coding Regions

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    BIOMEDICAL REPORTS 6: 211-216, 2017 De novo, systemic, deleterious amino acid substitutions are common in large cytoskeleton‑related protein coding regions REBECCA J. STOLL1, GRACE R. THOMPSON1, MOHAMMAD D. SAMY1 and GEORGE BLANCK1,2 1Department of Molecular Medicine, Morsani College of Medicine, University of South Florida; 2Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA Received June 13, 2016; Accepted October 31, 2016 DOI: 10.3892/br.2016.826 Abstract. Human mutagenesis is largely random, thus large Introduction coding regions, simply on the basis of probability, represent relatively large mutagenesis targets. Thus, we considered Genetic damage is largely random and therefore tends to the possibility that large cytoskeletal-protein related coding affect the larger, functional regions of the human genome regions (CPCRs), including extra-cellular matrix (ECM) more frequently than the smaller regions (1). For example, coding regions, would have systemic nucleotide variants that a systematic study has revealed that cancer fusion genes, on are not present in common SNP databases. Presumably, such average, are statistically, significantly larger than other human variants arose recently in development or in recent, preceding genes (2,3). The large introns of potential cancer fusion genes generations. Using matched breast cancer and blood-derived presumably allow for many different productive recombina- normal datasets from the cancer genome atlas, CPCR single tion opportunities, i.e., many recombinations that would allow nucleotide variants (SNVs) not present in the All SNPs(142) for exon juxtaposition and the generation of hybrid proteins. or 1000 Genomes databases were identified. Using the Protein Smaller cancer fusion genes tend to be associated with the rare Variation Effect Analyzer internet-based tool, it was discov- types of cancer, for example EWS RNA binding protein 1 in ered that apparent, systemic mutations (not shared among Ewing's sarcoma.