Genome-Wide Identification of Signaling Center Enhancers in the Developing Limb Julia E
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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. -
Original Articles the ALX4 Homeobox Gene Is Mutated in Patients With
916 J Med Genet 2000;37:916–920 J Med Genet: first published as 10.1136/jmg.37.12.916 on 1 December 2000. Downloaded from Original articles The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500) Wim Wuyts, Erna Cleiren, Tessa Homfray, Alberto Rasore-Quartino, Filip Vanhoenacker, Wim Van Hul Abstract Foramina parietalia permagna (FPP) (OMIM 168500) is caused by ossification defects in the parietal bones. Recently, it was shown that loss of function mutations in the MSX2 homeobox gene on chromo- some 5 are responsible for the presence of these lesions in some FPP patients. How- ever, the absence of MSX2 mutations in some of the FPP patients analysed and the presence of FPP associated with chromo- some 11p deletions in DEFECT 11 (OMIM 601224) patients or associated with Saethre-Chotzen syndrome suggests ge- netic heterogeneity for this disorder. Starting from a BAC/P1/cosmid contig of the DEFECT 11 region on chromosome 11, we have now isolated the ALX4 gene, a previously unidentified member of the http://jmg.bmj.com/ ALX homeobox gene family in humans. Mutation analysis of the ALX4 gene in three unrelated FPP families without the Department of MSX2 mutation identified mutations in Medical Genetics, two families, indicating that mutations in University of Antwerp, Figure 1 Radiograph illustrating the presence of foramina ALX4 could be responsible for these skull parietalia permagna (white arrows) in a patient of family Universiteitsplein 1, 6 12 2610 Antwerp, Belgium defects and suggesting further genetic 3. X rays of patients of families 1 and 2 have previously been published. -
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. -
Active Transport and Diffusion Barriers Restrict Joubert Syndrome-Associated ARL13B/ARL-13 to an Inv-Like Ciliary Membrane Subdomain
Active Transport and Diffusion Barriers Restrict Joubert Syndrome-Associated ARL13B/ARL-13 to an Inv-like Ciliary Membrane Subdomain Sebiha Cevik1, Anna A. W. M. Sanders1., Erwin Van Wijk2,3,4., Karsten Boldt5., Lara Clarke1, Jeroen van Reeuwijk3,6,7, Yuji Hori8, Nicola Horn5, Lisette Hetterschijt6, Anita Wdowicz1, Andrea Mullins1, Katarzyna Kida1, Oktay I. Kaplan1,9, Sylvia E. C. van Beersum3,6,7, Ka Man Wu3,6,7, Stef J. F. Letteboer3,6,7, Dorus A. Mans3,6,7, Toshiaki Katada8, Kenji Kontani8, Marius Ueffing5,10", Ronald Roepman3,6,7", Hannie Kremer2,3,4,6", Oliver E. Blacque1* 1 School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland, 2 Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands, 3 Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands, 4 Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands, 5 Division of Experimental Ophthalmology and Medical Proteome Center, Center of Ophthalmology, University of Tu¨bingen, Tu¨bingen, Germany, 6 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands, 7 Institute for Genetic and Metabolic Disease, Radboud University Medical Center, Nijmegen, The Netherlands, 8 Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan, 9 Berlin Institute for Medical Systems Biology (BIMSB) at Max-Delbru¨ck-Center for Molecular Medicine (MDC), Berlin, Germany, 10 Research Unit Protein Science, Helmholtz Zentrum Mu¨nchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany Abstract Cilia are microtubule-based cell appendages, serving motility, chemo-/mechano-/photo- sensation, and developmental signaling functions. -
Polycystin-1 Regulates ARHGAP35-Dependent Centrosomal Rhoa Activation and ROCK Signaling
Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling Andrew J. Streets, … , Philipp P. Prosseda, Albert C.M. Ong JCI Insight. 2020;5(16):e135385. https://doi.org/10.1172/jci.insight.135385. Research Article Genetics Nephrology Graphical abstract Find the latest version: https://jci.me/135385/pdf RESEARCH ARTICLE Polycystin-1 regulates ARHGAP35- dependent centrosomal RhoA activation and ROCK signaling Andrew J. Streets, Philipp P. Prosseda, and Albert C.M. Ong Kidney Genetics Group, Academic Nephrology Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom. Mutations in PKD1 (encoding for polycystin-1 [PC1]) are found in 80%–85% of patients with autosomal dominant polycystic kidney disease (ADPKD). We tested the hypothesis that changes in actin dynamics result from PKD1 mutations through dysregulation of compartmentalized centrosomal RhoA signaling mediated by specific RhoGAP (ARHGAP) proteins resulting in the complex cellular cystic phenotype. Initial studies revealed that the actin cytoskeleton was highly disorganized in cystic cells derived from patients with PKD1 and was associated with an increase in total and centrosomal active RhoA and ROCK signaling. Using cilia length as a phenotypic readout for centrosomal RhoA activity, we identified ARHGAP5, -29, and -35 as essential regulators of ciliation in normal human renal tubular cells. Importantly, a specific decrease in centrosomal ARHGAP35 was observed in PKD1-null cells using a centrosome-targeted proximity ligation assay and by dual immunofluorescence labeling. Finally, the ROCK inhibitor hydroxyfasudil reduced cyst expansion in both human PKD1 3D cyst assays and an inducible Pkd1 mouse model. In summary, we report a potentially novel interaction between PC1 and ARHGAP35 in the regulation of centrosomal RhoA activation and ROCK signaling. -
134 Mb (Almost the Same As the Size of Chromosome 10). It Is ~4–4.5% of the Total Human Genome
Chromosome 11 ©Chromosome Disorder Outreach Inc. (CDO) Technical genetic content provided by Dr. Iosif Lurie, M.D. Ph.D Medical Geneticist and CDO Medical Consultant/Advisor. Ideogram courtesy of the University of Washington Department of Pathology: ©1994 David Adler.hum_11.gif Introduction The genetic size of chromosome 11 is ~134 Mb (almost the same as the size of chromosome 10). It is ~4–4.5% of the total human genome. The length of its short arm is ~50 Mb; the length of its long arm in ~84 Mb. Chromosome 11 is a very gene–rich area. It contains ~1,500 genes. Mutations of ~200 of these genes are known to cause birth defects or some functional abnormalities. The short arm of chromosome 11 contains a region which is known to be imprinted. As a result duplications of this region will have different manifestations depending on the sex of the parent responsible for this defect. Phenotypes of persons with duplications of the maternal origin will be different from the phenotypes of the persons with a paternal duplication of the same area. There are ~1,400 patients with different structural abnormalities of chromosome 11 as the only abnormality or in association with abnormalities for other chromosomes. At least 800 of these patients had different deletions of chromosome 11. Deletions of the short arm have been reported in ~250 patients (including those with an additional imbalance); deletions of the long arm have been described in ~550 patients. There are two syndromes caused by deletions of the short arm (both of these syndromes have been known for several years) and one well–known syndrome caused by distal deletions of the long arm (Jacobsen syndrome). -
Characterization of Primary Cilia and Intraflagellar Transport 20 in the Epidermis
Characterization of Primary Cilia and Intraflagellar Transport 20 in the Epidermis Steven H. Su Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2020 © 2020 Steven H. Su All Rights Reserved Abstract Characterization of Primary Cilia and Intraflagellar Transport 20 in the Epidermis Steven H. Su Mammalian skin is a dynamic organ that constantly undergoes self-renewal during homeostasis and regenerates in response to injury. Crucial for the skin’s self-renewal and regenerative capabilities is the epidermis and its stem cell populations. Here we have interrogated the role of primary cilia and Intraflagellar Transport 20 (Ift20) in epidermal development as well as during homeostasis and wound healing in postnatal, adult skin. Using a transgenic mouse model with fluorescent markers for primary cilia and basal bodies, we characterized epidermal primary cilia during embryonic development as well as in postnatal and adult skin and find that both the Interfollicular Epidermis (IFE) and hair follicles (HFs) are highly ciliated throughout development as well as in postnatal and adult skin. Leveraging this transgenic mouse, we also developed a technique for live imaging of epidermal primary cilia in ex vivo mouse embryos and discovered that epidermal primary cilia undergo ectocytosis, a ciliary mechanism previously only observed in vitro. We also generated a mouse model for targeted ablation of Ift20 in the hair follicle stem cells (HF-SCs) of adult mice. We find that loss of Ift20 in HF-SCs inhibits ciliogenesis, as expected, but strikingly it also inhibits hair regrowth. -
Genetic Interaction of Gli3 and Alx4 During Limb Development
Int. J. Dev. Biol. 49: 443-448 (2005) doi: 10.1387/ijdb.051984lp Short Communication Genetic interaction of Gli3 and Alx4 during limb development LIA PANMAN*,a, THIJS DRENTHb, PASCAL TEWELSCHERc, AIMÉE ZUNIGA1 and ROLF ZELLER1 Department of Developmental Biology, Utrecht University, Utrecht, The Netherlands and 1Developmental Genetics, DKBW Centre for Biomedicine, University of Basel Medical School, Basel, Switzerland. ABSTRACT The Gli3 and Alx4 transcriptional regulators are expressed in the anterior limb bud mesenchyme and their disruption in mice results in preaxial polydactyly. While the polydactylous phenotype of Alx4 deficient limb buds depends on SHH, the one of Gli3 deficient limb buds is completely independent of SHH signalling, suggesting that these genes act in parallel pathways. Analysis of limb buds lacking both Gli3 and Alx4 now shows that these two genes interact during limb skeletal morphogenesis. In addition to the defects in single mutants, the stylopod is severely malformed and the anterior element of the zeugopod is lost in double mutant limbs. However, limb bud patterning in Gli3-/- ; Alx4-/- double mutant embryos is not affected more than in single mutants as the expression domains of key regulators remain the same. Most interestingly, the loss of the severe preaxial polydactyly characteristic of Gli3 -/- limbs in double mutant embryos establishes that this type of polydactyly requires Alx4 function. KEY WORDS: Hox gene, limb development, preaxial polydactyly, radius, SHH, tibia The semi-dominant mouse mutations Extra-toes ( Xt ) and Strong’s forms in limbs lacking both Alx4 and Shh (for details see te Luxoid (Lst ), are loss-of-function mutations disrupting the zinc- Welscher et al., 2002b). -
Ciliary Genes Arl13b, Ahi1 and Cc2d2a Differentially Modify Expression of Visual Acuity
bioRxiv preprint doi: https://doi.org/10.1101/569822; this version posted March 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Ciliary Genes arl13b, ahi1 and cc2d2a Differentially Modify Expression of Visual Acuity 2 Phenotypes but do not Enhance Retinal Degeneration due to Mutation of cep290 in Zebrafish 3 4 Short title: Retinal degeneration in cep290 mutant zebrafish 5 6 7 Emma M. Lessieur1,2,4, Ping Song1,4, Gabrielle C. Nivar1, 8 Ellen M. Piccillo1, Joseph Fogerty1, Richard Rozic3, and Brian D. Perkins1,2 9 10 1Department of Ophthalmic Research, Cole Eye Institute, 11 Cleveland Clinic, Cleveland, OH 44195 United States 12 2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, 13 Case Western Reserve University, Cleveland, OH 44195 United States 14 3Department of Biomedical Engineering, Lerner Research Institute, 15 Cleveland Clinic, Cleveland, OH 44195 United States 16 17 4These authors contributed equally to this work 18 Correspondence to: 19 Brian D. Perkins, Ph.D. 20 Department of Ophthalmic Research 21 Cleveland Clinic 22 9500 Euclid Ave 23 Building i3-156 24 Cleveland, OH 44195, USA 25 (Ph) 216-444-9683 26 (Fax) 216-445-3670 27 [email protected] 28 29 1 bioRxiv preprint doi: https://doi.org/10.1101/569822; this version posted March 6, 2019. 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. -
Ahi1 Promotes Arl13b Ciliary Recruitment, Regulates Arl13b Stability and Is Required for Normal Cell Migration Jesúsmuñoz-Estrada1 and Russell J
© 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs230680. doi:10.1242/jcs.230680 RESEARCH ARTICLE Ahi1 promotes Arl13b ciliary recruitment, regulates Arl13b stability and is required for normal cell migration JesúsMuñoz-Estrada1 and Russell J. Ferland1,2,* ABSTRACT (TZ), and participates in the formation of primary cilia in epithelial Mutations in the Abelson-helper integration site 1 (AHI1) gene are cells (Hsiao et al., 2009). Recently, JBTS has been proposed to associated with neurological/neuropsychiatric disorders, and cause result from disruption of the ciliary TZ architecture, leading to the neurodevelopmental ciliopathy Joubert syndrome (JBTS). Here, defective ciliary signaling (Shi et al., 2017). we show that deletion of the transition zone (TZ) protein Ahi1 in The primary cilium, a slender microtubule-based extension mouse embryonic fibroblasts (MEFs) has a small effect on cilia (axoneme) of the cell membrane, is critical for embryonic formation. However, Ahi1 loss in these cells results in: (1) reduced development and tissue homeostasis (Goetz and Anderson, 2010). localization of the JBTS-associated protein Arl13b to the ciliary In non-dividing cells that form cilia, migration and docking of the membrane, (2) decreased sonic hedgehog signaling, (3) and an basal body (a modified mother centriole) to the apical membrane, abnormally elongated ciliary axoneme accompanied by an increase intraflagellar transport (IFT) and microtubule dynamics are required in ciliary IFT88 concentrations. While no changes in Arl13b levels are for assembly and elongation of the axoneme (Rosenbaum and detected in crude cell membrane extracts, loss of Ahi1 significantly Witman, 2002; Sorokin, 1962; Stephens, 1997). -
PKD2 Is an Essential Ion Channel Subunit in the Primary Cilium of the Renal Collecting Duct Epithelium
bioRxiv preprint doi: https://doi.org/10.1101/215814; this version posted November 7, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 2 PKD2 is an essential ion channel subunit in the primary cilium 3 of the renal collecting duct epithelium 4 5 6 Xiaowen Liu1,4, Thuy Vien2, Jingjing Duan1,4, Shu-Hsien Sheu1,4, Paul G. DeCaen2,3 and David E. 7 Clapham1,3,4 8 9 1. Howard Hughes Medical Institute, Department of Cardiology, Boston Children's Hospital, 10 320 Longwood Avenue, Boston, MA 02115, USA; Department of Neurobiology, Harvard 11 Medical School, Boston, MA 02115, USA 12 2. Northwestern University, Feinberg School of Medicine, Department of Pharmacology, 320 13 East Superior Street, Chicago, Illinois 60611 14 3. Correspondence should be addressed to P.G.D. or D.E.C. (email: 15 [email protected] or [email protected]) 16 4. Current address: Janelia Research Campus, HHMI, 19700 Helix Drive, Ashburn, VA 20147 17 18 Abbreviations used: 19 - Pkd1 or Pkd2 (lower case letters): when referring to polycystin genes 20 - PKD1 or PKD2 (capital letters): when referring to polycystin proteins 21 - cPkd1: a mouse expressing Pax8rtTA; TetO-cre; Pkd1fl/fl 22 - cPkd2: a mouse expressing Pax8rtTA; TetO-cre; Pkd2fl/fl 23 - Arl13B-EGFPtg: a transgenic mouse expressing multiple copies of the cilia-localized 24 Arl13B-EGFP gene 25 - pIMCD: primary distal collecting duct tubule epithelial cells isolated from mice used 26 in the study (Arl13B-EGFPtg; Arl13B-EGFPtg:cPkd1; Arl13B-EGFPtg:cPkd2) 2+ 27 - [free-Ca ]in: internal free calcium concentration (cilioplasm or cytoplasm) 28 1 bioRxiv preprint doi: https://doi.org/10.1101/215814; this version posted November 7, 2017. -
Construction of a Natural Panel of 11P11.2 Deletions and Further Delineation of the Critical Region Involved in Potocki–Shaffer Syndrome
European Journal of Human Genetics (2005) 13, 528–540 & 2005 Nature Publishing Group All rights reserved 1018-4813/05 $30.00 www.nature.com/ejhg ARTICLE Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki–Shaffer syndrome Keiko Wakui1,12, Giuliana Gregato2,3,12, Blake C Ballif2, Caron D Glotzbach2,4, Kristen A Bailey2,4, Pao-Lin Kuo5, Whui-Chen Sue6, Leslie J Sheffield7, Mira Irons8, Enrique G Gomez9, Jacqueline T Hecht10, Lorraine Potocki1,11 and Lisa G Shaffer*,2,4 1Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA; 2Health Research and Education Center, Washington State University, Spokane, WA, USA; 3Dip. Patologia Umana ed Ereditaria, Sez. Biologia Generale e Genetica Medica, Universita` degli Studi di Pavia, Italy; 4Sacred Heart Medical Center, Spokane, WA, USA; 5Department of Obstetrics and Gynecology, National Cheng-Kung University Medical College, Taiwan; 6Department of Pediatrics, Taipei Municipal Women and Children’s Hospital, Taiwan; 7Genetic Health Services Victoria, Murdoch Children’s Research Institute, Department of Paediatrics, University of Melbourne, Victoria, Australia; 8Division of Genetics, Department of Medicine, Children’s Hospital, Harvard Medical School, Boston, MA, USA; 9Area de Gene´tica, Centro de Desarrollo Infantil y Departamento de Pediatrı´a Hospital Materno Infantil-Hospital Regional Universitario ‘Infanta Cristina’, Badajoz, Spain; 10Department of Pediatrics, University of Texas Medical School at Houston, TX, USA; 11Texas Children’s Hospital, Houston, TX, USA Potocki–Shaffer syndrome (PSS) is a contiguous gene deletion syndrome that results from haploinsufficiency of at least two genes within the short arm of chromosome 11[del(11)(p11.2p12)].