DOCSLIB.ORG

The Genetic Basis of Human Craniosynostosis Syndromes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Genetic Basis of Human Craniosynostosis Syndromes 25'1ò.q,8 .{ |ì Á. The Genetic Basis of Human Craniosynostosis syndromes. Georgina Hollway BSc. (Hons.) Department of Paediatrics University of Adelaide A thesis submitted for the degree of Doctor of PhilosoPhy April 1998 ll TABLE OF CONTENTS Page Summary iv Declaration vi List of Publications vii Abbreviations viii Acknowledgments X Chapter l: Introduction I Chapter 2.Matenals and Methods 25 Chapter 3: Linkage Mapping of a Craniosynostosis Syndrome 43 Chapter 4: Mutation Search inMSXI 62 Chapter 5: Mutation Detection inFGFR3 86 Chapter 6: Exploration of the Functional Implications of the Pro25OArg Mutation of FGFR3 by High Sensitivity Immunofluoresence Flow Cytometry tt7 Chapter 7: Mutation Detection in FGFR2 and Identification of 3 Novel Mutations 736 Chapter 8: Mutation Screening inFGFS t67 111 Chapter 9: Detection of the Pro25OArg Mutation of FGFR3 m patients with Craniosynostosis and Deafness 180 Chapter 10. Conclusion 190 References 195 Appendices 1V SUMMARY Craniosynostosis is the premature fusion of one or more sutures of the skull. This can result in the distortion of the shape of the head and face, and affects an estimated 0.25 to 1.6 children per 1,000 live births. The aims of this project were to identify genes involved in craniosynostosis and to characterise mutations of these genes. To this end, linkage mapping was undertaken in a craniosynostosis pedigree and a gene was localised to chromosomal region 4p16, distal to the marker D45394. This interval contained two plausible candidate genes, MSXI and FGFR3. The localisation to 4pl6 was the first evidence for the presence of a craniosynostosis syndrome in this region of the genome. These candidate genes were screened for mutations using single strand confirmation analysis, heteroduplex analysis and sequencing. Three polymorphisms were identified in MSXI; however, no mutations were detected. Two polymorphisms were identified in FGFR3 before a candidate mutation in FGFR3 was found in a number of craniosynostosis patients, by researchers in North America. This mutation, C749G in FGFR3 (Pro250Arg) was then demonstrated to segregate with the affected members of the craniosynostosis pedigree localised to chromosomal region 4p16. Thg mutation was found in a further large pedigree in which autosomal deafness was the major feature, suggesting that the Pro25l{rg mutation may account for a proportion of autosomal dominant deafüess in the population. The Pro25gArg mutation of FGFR3 was found in fìve additional unrelated patients and is now recognised as a relatively cofltmon recurrent mutation among patients presenting to craniofacial clinics. Determination of the molecular defect responsible for this craniosynostosis syndrome, led to an investigation of the effect of the mutation on the protein and how it results in craniosynostosis. Antisera to part of the extracellular region of the FGFR3 protein were used in flow cytometry experiments on skin fibroblast cells from an affected member of the craniosynostosis pedigree and from normal controls. The hypothesis was that the receptors V from affected and unaffected cells would be distinguishable in this way, to allow further investigation. However, it was not possible to reliably detect a difference. In parallel to the FGFR3 craniosynostosis study, patients with a clinical diagnosis consistent with FGFR2 craniosynostosis syndromes were examined for molecular defects. FGFR2 mutations were found n 12 unrelated Apert patients, 8 unrelated Crouzon patients, 3 unrelated Pfeiffer patients and 6 unrelated patients with uncertain diagnoses. Three of the mutations found were novel; T8754, T797C and G(-l)C (a splice site mutation). Characterisationof FGFR2 mutations will identify which regions of the gene are functionally important and will form the basis for the study of the genotype-phenotype relations in craniosynostosis disorders. The genes causing Apert, Crouzon, Jackson Weiss, Pfeiffer and Saethre Chotzen syndromes were identified, by others, while this project was proceeding. Work carried out by the candidate and others during the course of this project elucidated the genetic basis for Craniosynostosis Adelaide Type (FGFR3 craniosynostosis). In addition, the candidate characterised FGFR2 craniosynostosis mutations to further elucidate the molecular genetic basis for that group ofdisorders. vl DECLARATION accepted for the award of any other degree This thesis contains no material which has been institution and, to the best of my knowledge or dþloma in any university or other tertiary person' previously published or written by another and beliet this thesis contains no material in the text' except where due reference has been made deposited in the University Library' being I give consent to this copy of my thesis, when available for loan and photocopying' refers to Georgina Hollway' Throughout the thesis, the term'the candidate' GEORGINAHOLLWAY 30.4.98 vll LIST OF PUBLICATIONS Some of the work presented in this thesis has been published, or accepted for publication and is in press. Reprints or final manuscripts as accepted for publication of these papers are included as appendices to this thesis. Hollway, G.E. , Phillips, H.4., Ades, L.C.,Haan E.A. and Mulley, J.C. (1995) Localisation of craniosynostosis Adelaide type to 4p16. Human Molecular Genetics 4,681-683. Hollway, G.8., Suthers, G.K., Haan, E.4., Thompson, 8., David, DJ., Gecz, J. and Mulley, J.C. (1997) Mutation detection in FGFR2 craniosynostosis syndromes. Human Genetics 99,251-255. Muenke, M., Gripp, K.W., McDonald-McGinn, D.M., Gaudenz, K., Whitaker, L.4., Bartlett, S.P., Markowitz, R.I., Robin, N.H., Nwokoro, N., Mulvihill, J.J., Losken, H.Vy'., Mulliken, J.8., Guttmacher, A.8., V/ilroy, R.S., Clarke, L.4., HollwãY, G., Adès, L.C.,Haan, E.4., Mulley, J.C., Cohen Jr, M.M., Bellus, G.4., Francomano, C.4., Moloney, D.M., Wall, S.4., Wilkie, A.O.M. and Zackai, E.H. (1997) A unique point mutation in the Fibroblast Growth Factor Receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. American Journal of Human Genetics 60,555-564. Hollway, G.E., Suthers, G.K., Battese, K.M., Turner, 4.M., David, D'.J. and Mulley, J.C. (1998) Deafness due to Pro25l{rg mutation of FGFR3. The Lancet 351,877-878 Hollway, G.E. and Mulley, J.C. Polymorphic Variants within the HomeoboxGeneMSXl Clinical Genetics - accepted for publication. vl11 ABBRE\rIATIONS A - adenine ¡cr "lldctP - alphalabelled deoxyadenosine triphosphate AC - dinucleotide repeat microsatellite ACH - achondroplasia bp, Kb - base pairs, kilobase pairs C - cytosine CAT - Craniosynostosis Adelaide type Ci, pCi - Curies, micro Curies cM - centimorgan (the genetic distance within which there is expected to be one crossover every 100 meioses) CEPH - Centre d'Etude du Polymorphisme Humain (Centre for the Study of Human Polymorphism) CHRI - Child Health Research Institute, WCH, North Adelaide, South Australia CVS - chorionic villus sample EDTA - ethylenediaminetetra-acetic acid FGF - fibroblast growth factor FGFR - fibroblast growth factor receptor G - guanine g, frB,ug, trg, pg - gram) milligram, microgram, nanogram, picogram HA - heteroduplex analysis IPTG - isopropylthio B -galacto side JW - Jackson Weiss JWS - Jackson Weiss syndrome l, ml, pl - litre, millilitre, microlitre LCL - lymphoblastoid cell line (derived from a eukaryotic cell) lod score - the decimal logarithm of the likelihood ratio of linkage versus no linkage M, mM - moles per litre, millimoles per litre MDE - mutation detection enhancement 1X MgCl2 - magnesium chloride NaAc - sodium acetafe NaNO¡ - sodium nitrate NIH - National Institutes of Health OD260 - optical density at 260 nanometres PCR - polymerase chain reaction PE-SA - phycoerythrin conjugated to streptavidin pH - negative logarithm of the hydrogen ion concentration (in moles per litre) RFLP - restriction fragment polymorphism rpm - revolutions per minute RT - reverse transcriptase RT PCR - reverse transcription polymerase chain reaction SCS - Saethre Chotzen syndrome SDS - sodium dodecyl sulphate SPSS sequencing - solid phase single strand sequencing SSCA (SSCP) - single stranded conformation analysis (polymorphism) T - thymidine TD - thanatophoric dysplasia TEMED - tetramethylethylenediamine Tris - tris[hydroxymethyl]amino methane VNTR - variable number of tandem repeats (also known as minisatellite) WCH - Women's and Children's Hospital, North Adelaide, South Australia X-gal - 5-bromo-4-chloro-3-indoyl-B-galactoside x ACKNOWLEDGMENTS The work presented in this thesis was carried out in the Department of Cytogenetics and Molecular Genetics at the Women's and Children's Hospital, Adelaide. I am grateful for the financial support I received from an Australian Postgraduate Award and from the Department of Cytogenetics and Molecular Genetics. I would like to thank my principal supervisor Dr John Mulley for his advice, encouragement and humour throughout this project. I would also like to thank Prof Grant Sutherland for the opportunity to conduct this research in the department and for his valuable advice. Many clinicians have contributed to this project and their work was essential for the project to proceed. In particular I would like to thank Dr Graeme Suthers for his keen interest in the craniosynostosis research. I am extremely grateful to Prof Heddy Zola fot allowing me to conduct flow cytometry experiments in the Child Health Research Institute, and for many of the reagents necessary for this. I am also very grateful to Prof Michael Hayman for sending a sample of the 58141 antiserum fromNew
Load more

Recommended publications
  • Type II Familial Synpolydactyly: Report on Two Families with an Emphasis on Variations of Expression
    European Journal of Human Genetics (2011) 19, 112–114 & 2011 Macmillan Publishers Limited All rights reserved 1018-4813/11 www.nature.com/ejhg SHORT REPORT Type II familial synpolydactyly: report on two families with an emphasis on variations of expression Mohammad M Al-Qattan*,1 Type II familial synpolydactyly is rare and is known to have variable expression. However, no previous papers have attempted to review these variations. The aim of this paper was to review these variations and show several of these variable expressions in two families. The classic features of type II familial synpolydactyly are bilateral synpolydactyly of the third web spaces of the hands and bilateral synpolydactyly of the fourth web spaces of the feet. Several members of the two families reported in this paper showed the following variations: the third web spaces of the hands showing syndactyly without the polydactyly, normal feet, concurrent polydactyly of the little finger, concurrent clinodactyly of the little finger and the ‘homozygous’ phenotype. It was concluded that variable expressions of type II familial synpolydactyly are common and awareness of such variations is important to clinicians. European Journal of Human Genetics (2011) 19, 112–114; doi:10.1038/ejhg.2010.127; published online 18 August 2010 Keywords: type II familial syndactyly; inherited synpolydactyly; variations of expression INTRODUCTION CASE REPORTS Type II familial synpolydactyly is rare and it has been reported in o30 The first family families.1–12 It is characterized by bilateral synpolydactyly of the third The family had a history of synpolydactyly type II for several web spaces of the hands and bilateral synpolydactyly of the fourth web generations on the mother’s side (Table 1).
    [Show full text]
  • The Genetic Basis for Skeletal Diseases
    insight review articles The genetic basis for skeletal diseases Elazar Zelzer & Bjorn R. Olsen Harvard Medical School, Department of Cell Biology, 240 Longwood Avenue, Boston, Massachusetts 02115, USA (e-mail: [email protected]) We walk, run, work and play, paying little attention to our bones, their joints and their muscle connections, because the system works. Evolution has refined robust genetic mechanisms for skeletal development and growth that are able to direct the formation of a complex, yet wonderfully adaptable organ system. How is it done? Recent studies of rare genetic diseases have identified many of the critical transcription factors and signalling pathways specifying the normal development of bones, confirming the wisdom of William Harvey when he said: “nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path”. enetic studies of diseases that affect skeletal differentiation to cartilage cells (chondrocytes) or bone cells development and growth are providing (osteoblasts) within the condensations. Subsequent growth invaluable insights into the roles not only of during the organogenesis phase generates cartilage models individual genes, but also of entire (anlagen) of future bones (as in limb bones) or membranous developmental pathways. Different mutations bones (as in the cranial vault) (Fig. 1). The cartilage anlagen Gin the same gene may result in a range of abnormalities, are replaced by bone and marrow in a process called endo- and disease ‘families’ are frequently caused by mutations in chondral ossification. Finally, a process of growth and components of the same pathway.
    [Show full text]
  • Genetics of Congenital Hand Anomalies
    G. C. Schwabe1 S. Mundlos2 Genetics of Congenital Hand Anomalies Die Genetik angeborener Handfehlbildungen Original Article Abstract Zusammenfassung Congenital limb malformations exhibit a wide spectrum of phe- Angeborene Handfehlbildungen sind durch ein breites Spektrum notypic manifestations and may occur as an isolated malforma- an phänotypischen Manifestationen gekennzeichnet. Sie treten tion and as part of a syndrome. They are individually rare, but als isolierte Malformation oder als Teil verschiedener Syndrome due to their overall frequency and severity they are of clinical auf. Die einzelnen Formen kongenitaler Handfehlbildungen sind relevance. In recent years, increasing knowledge of the molecu- selten, besitzen aber aufgrund ihrer Häufigkeit insgesamt und lar basis of embryonic development has significantly enhanced der hohen Belastung für Betroffene erhebliche klinische Rele- our understanding of congenital limb malformations. In addi- vanz. Die fortschreitende Erkenntnis über die molekularen Me- tion, genetic studies have revealed the molecular basis of an in- chanismen der Embryonalentwicklung haben in den letzten Jah- creasing number of conditions with primary or secondary limb ren wesentlich dazu beigetragen, die genetischen Ursachen kon- involvement. The molecular findings have led to a regrouping of genitaler Malformationen besser zu verstehen. Der hohe Grad an malformations in genetic terms. However, the establishment of phänotypischer Variabilität kongenitaler Handfehlbildungen er- precise genotype-phenotype correlations for limb malforma- schwert jedoch eine Etablierung präziser Genotyp-Phänotyp- tions is difficult due to the high degree of phenotypic variability. Korrelationen. In diesem Übersichtsartikel präsentieren wir das We present an overview of congenital limb malformations based Spektrum kongenitaler Malformationen, basierend auf einer ent- 85 on an anatomic and genetic concept reflecting recent molecular wicklungsbiologischen, anatomischen und genetischen Klassifi- and developmental insights.
    [Show full text]
  • Angeborene Fehlbildungen Der Extremitäten
    Aus der Klinik für Orthopädie (Direktor: Prof. Dr. med. J. Hassenpflug) der Medizinischen Fakultät der Christian-Albrechts-Universität zu Kiel Die angeborenen Fehlbildungen der oberen und unteren Extremitäten in der Orthopädischen Universitätsklinik Kiel von 1974-2001 Inauguraldissertation zur Erlangung der Doktorwürde vorgelegt von Karsten Naused aus Wolfenbüttel Kiel 2014 1. Berichterstatter: Prof. Dr. J. Hassenpflug, Klinik für Orthopädie 2. Berichterstatter: Prof. Dr. M. Schrappe, Klinik für Allgemeine Pädiatrie Tag der mündlichen Prüfung: 12.06.2014 Zum Druck genehmigt, Kiel, den 12.06.2014 gez.: PD Dr. S. Lippross, Klinik Unfallchirurgie (Prüfer) Prof. Dr. A. Seekamp, Klinik Unfallchirurgie (Beisitzer) Prof. Dr. Johann Roider, Vorsitzender des Ausschusses für Promotion Inhaltsverzeichnis 1. Einleitung Seite 1.1 Vorbemerkung.................................................................................................1 1.2 Historisches.....................................................................................................2 1.3 Embryologie.....................................................................................................3 1.4 Ätiologie und Pathogenese..............................................................................6 2. Patientengut und Methode 2.1 Quellen der Patientendaten...........................................................................10 2.2 Dokumentation der Daten..............................................................................12 2.3 Datenabfrage.................................................................................................13
    [Show full text]
  • Polydactyly of the Hand
    A Review Paper Polydactyly of the Hand Katherine C. Faust, MD, Tara Kimbrough, BS, Jean Evans Oakes, MD, J. Ollie Edmunds, MD, and Donald C. Faust, MD cleft lip/palate, and spina bifida. Thumb duplication occurs in Abstract 0.08 to 1.4 per 1000 live births and is more common in Ameri- Polydactyly is considered either the most or second can Indians and Asians than in other races.5,10 It occurs in a most (after syndactyly) common congenital hand ab- male-to-female ratio of 2.5 to 1 and is most often unilateral.5 normality. Polydactyly is not simply a duplication; the Postaxial polydactyly is predominant in black infants; it is most anatomy is abnormal with hypoplastic structures, ab- often inherited in an autosomal dominant fashion, if isolated, 1 normally contoured joints, and anomalous tendon and or in an autosomal recessive pattern, if syndromic. A prospec- ligament insertions. There are many ways to classify tive San Diego study of 11,161 newborns found postaxial type polydactyly, and surgical options range from simple B polydactyly in 1 per 531 live births (1 per 143 black infants, excision to complicated bone, ligament, and tendon 1 per 1339 white infants); 76% of cases were bilateral, and 3 realignments. The prevalence of polydactyly makes it 86% had a positive family history. In patients of non-African descent, it is associated with anomalies in other organs. Central important for orthopedic surgeons to understand the duplication is rare and often autosomal dominant.5,10 basic tenets of the abnormality. Genetics and Development As early as 1896, the heritability of polydactyly was noted.11 As olydactyly is the presence of extra digits.
    [Show full text]
  • Evolution of Morphology: Modifications to Size and Pattern
    Evolution of Morphology: Modifications to Size and Pattern The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Uygur, Aysu N. 2014. Evolution of Morphology: Modifications to Size and Pattern. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12274611 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Evolution of Morphology: Modifications to Size and Pattern A dissertation presented by Aysu N. Uygur to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Genetics Harvard University Cambridge, Massachusetts May, 2014 iii © 2014 by Aysu N. Uygur All Rights Reserved iv Dissertation Advisor: Dr. Clifford J. Tabin Aysu N. Uygur Evolution of Morphology: Modifications to Size and Pattern Abstract A remarkable property of developing organisms is the consistency and robustness within the formation of the body plan. In many animals, morphological pattern formation is orchestrated by conserved signaling pathways, through a process of strict spatio-temporal regulation of cell fate specification. Although morphological patterns have been the focus of both classical and recent studies, little is known about how this robust process is modified throughout evolution to accomodate different morphological adaptations. In this dissertation, I first examine how morphological patterns are conserved throughout the enourmous diversity of size in animal kingdom.
    [Show full text]
  • Congenital Malformations in Sea Turtles: Puzzling Interplay Between Genes and Environment
    animals Review Congenital Malformations in Sea Turtles: Puzzling Interplay between Genes and Environment Rodolfo Martín-del-Campo 1, María Fernanda Calderón-Campuzano 2, Isaías Rojas-Lleonart 3, Raquel Briseño-Dueñas 2,4 and Alejandra García-Gasca 5,* 1 Department of Oral Health Sciences, Faculty of Dentistry, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; [email protected] 2 Marine Turtle Programme, Instituto de Ciencias del Mar y Limnología-UNAM-FONATUR, Mazatlán, Sinaloa 82040, Mexico; [email protected] (M.F.C.-C.); [email protected] (R.B.-D.) 3 Universidad Central “Martha Abreu” de las Villas (IRL), CUM Remedios, Villa Clara 52700, Cuba; [email protected] 4 Banco de Información sobre Tortugas Marinas (BITMAR), Unidad Académica Mazatlán, Instituto de Ciencias del Mar y Limnología-UNAM, Mazatlán, Sinaloa 82040, Mexico 5 Laboratory of Molecular and Cellular Biology, Centro de Investigación en Alimentación y Desarrollo, Mazatlán, Sinaloa 82112, Mexico * Correspondence: [email protected]; Tel.: +52-669-989-8700 Simple Summary: Congenital malformations can lead to embryonic mortality in many species, and sea turtles are no exception. Genetic and/or environmental alterations occur during early develop- ment in the embryo, and may produce aberrant phenotypes, many of which are incompatible with life. Causes of malformations are multifactorial; genetic factors may include mutations, chromosomal aberrations, and inbreeding effects, whereas non-genetic factors may include nutrition, hyperthermia, low moisture, radiation, and contamination. It is possible to monitor and control some of these Citation: Martín-del-Campo, R.; Calderón-Campuzano, M.F.; factors (such as temperature and humidity) in nesting beaches, and toxic compounds in feeding Rojas-Lleonart, I.; Briseño-Dueñas, R.; areas, which can be transferred to the embryo through their lipophilic properties.
    [Show full text]
  • Review Article Cleidocranial Dysplasia: Clinical and Molecular Genetics
    J Med Genet 1999;36:177–182 177 Review article Cleidocranial dysplasia: clinical and molecular genetics Stefan Mundlos Abstract Chinese named Arnold, was probably de- Cleidocranial dysplasia (CCD) (MIM scribed by Jackson.6 He was able to trace 356 119600) is an autosomal dominant skeletal members of this family of whom 70 were dysplasia characterised by abnormal aVected with the “Arnold Head”. CCD was clavicles, patent sutures and fontanelles, originally thought to involve only bones of supernumerary teeth, short stature, and a membranous origin. More recent and detailed variety of other skeletal changes. The dis- clinical investigations have shown that CCD is ease gene has been mapped to chromo- a generalised skeletal dysplasia aVecting not some 6p21 within a region containing only the clavicles and the skull but the entire CBFA1, a member of the runt family of skeleton. CCD was therefore considered to be transcription factors. Mutations in the a dysplasia rather than a dysostosis.7 Skeletal CBFA1 gene that presumably lead to syn- abnormalities commonly found include cla- thesis of an inactive gene product were vicular aplasia/hypoplasia, bell shaped thorax, identified in patients with CCD. The func- enlarged calvaria with frontal bossing and open tion of CBFA1 during skeletal develop- fontanelles, Wormian bones, brachydactyly ment was further elucidated by the with hypoplastic distal phalanges, hypoplasia of generation of mutated mice in which the the pelvis with widened symphysis pubis, Cbfa1 gene locus was targeted. Loss of one severe dental anomalies, and short stature. The Cbfa1 allele (+/-) leads to a phenotype very changes suggest that the gene responsible is not similar to human CCD, featuring hypo- only active during early development, as plasia of the clavicles and patent fonta- implied by changes in the shape or number of nelles.
    [Show full text]
  • 25. C:\Documents and Settings\Kwang-Il\My
    The human disease network Goh K-I, Cusick ME, Valle D, Childs B, Vidal M, Barabasi′ A-L (2007) Proc Natl Acad Sci USA 104:8685-8690 Disorder Class Bone Coats Cancer Urolithiasise Osteopetrosis disease NDP Caffey van_Buchem Exudative Cardiovascular disease disease vitreoretinopathy Norrie SLC34A1 disease 439 LRP5 Connective tissue disorder Nevo Hyperostosis, syndrome COL1A1 endosteal Dermatological PLOD1 217 PAX9 Oligodontia Osteogenesis Osteoporosis 1164 Developmental Ehlers-Danlos imperfecta syndrome Arthropathy COL3A1 Hypodontia Ear, Nose, Throat Aneurysm, COL1A2 familial_arterial Myasthenic Witkop 733 syndrome Heart syndrome Pseudoachondroplasia Endocrine 3-methylglutaconicaciduria OPA3 WISP3 Optic Marfan block MSX1 atrophy OPA1 Aortic syndrome Paramyotonia Sick_sinus Gastrointestinal aneurysm congenita syndrome 3558 Intervertebral_disc Brugada SCN4A disease syndrome Syndactyly Spondyloepiphyseal COMP COL9A2 Hematological Glaucoma Weill-Marchesani Shprintzen-Goldberg Cramps, SCN5A Zlotogora-Ogur Cleft dysplasia syndrome syndrome potassium-aggravated Myotonia 2785 syndrome palate Parkes_Weber Basal_cell FBN1 congenita Oculodentodigital COL9A3 1432 Immunological 1414 CYP1B1 syndrome nevus_syndrome MASS Hypokalemic Acquired dysplasia Peters long_QT_syndrome Epiphyseal FLNB RASA1 PTCH Keratitis syndrome periodic MATN3 Metabolic SHH anomaly Eye Ectopia Thyrotoxic paralysis dysplasia Atelosteogenesis anomalies Marshall Larson Capillary Basal_cell Holoprosencephaly Coloboma, periodic KCNH2 PVRL1 malformations GJA1 Incontinentia syndrome SLC26A2
    [Show full text]
  • Zur Morphologie Und Vererbung Des Polydaktylie-Luxations-Syndroms Bei Dem Wistar-Rattenstamm Shoe: WIST (Shoe)
    Tierärztliche Hochschule Hannover Zur Morphologie und Vererbung des Polydaktylie- Luxations-Syndroms bei dem Wistar-Rattenstamm Shoe:WIST(Shoe) INAUGURAL-DISSERTATION zur Erlangung des Grades einer Doktorin der Veterinärmedizin - Doctor medicinae veterinariae - (Dr. med. vet.) vorgelegt von Christine Krüger Hameln Hannover 2012 Wissenschaftliche Betreuung: Univ.-Prof. Dr. med. vet. Wolfgang Baumgärtner, Ph.D., Institut für Pathologie, Stiftung Tierärztliche Hochschule Hannover 1. Gutachter: Univ.-Prof. Dr. med. vet. Wolfgang Baumgärtner, Ph. D. 2. Gutachter: Univ.-Prof. Dr. med. vet. Michael Fehr Tag der mündlichen Prüfung: 29.11.2012 meinen Eltern 1 Einleitung ........................................................................................................... 1 2 Literaturübersicht ...............................................................................................3 2.1 Embryonale Gliedmaßenentwicklung ........................................................... 3 2.2 Gliedmaßenfehlbildungen des Menschen .................................................... 4 2.2.1 Klassifikation ......................................................................................... 4 2.2.2 Ätiologie ................................................................................................ 7 2.2.3 Häufigkeit ............................................................................................ 13 2.2.4 Fehlbildungen des Zeugo- und Autopodium beim Menschen ............. 14 2.2.4.1 Zeugopodium ..............................................................................
    [Show full text]
  • Triplet Repeat Diseases
    1 Triplet Repeat Diseases Stephan J. Guyenet and Albert R. La Spada University of Washington, Seattle, WA 98195 1 A Novel Mechanism of Genetic Mutation Emerges 3 1.1 Repeat Sequences of All Types and Sizes 3 1.2 Trinucleotide Repeat Expansion as a Cause of Disease: Unique Features Explain Unusual Genetics 4 2 Repeat Diseases and Their Classification 5 2.1 Summary of Repeat Diseases 5 2.2 Differences in Repeat Sequence Composition and Location within Gene 6 2.3 Classification Based upon Mechanism of Pathogenesis and Nature of Mutation 6 3 Type 1: The CAG/Polyglutamine Repeat Diseases 9 3.1 Spinal and Bulbar Muscular Atrophy 9 3.2 Huntington’s Disease 12 3.3 Dentatorubral Pallidoluysian Atrophy 15 3.4 Spinocerebellar Ataxia Type 1 16 3.5 Spinocerebellar Ataxia Type 2 18 3.6 Spinocerebellar Ataxia Type 3/Machado–Joseph Disease 19 3.7 Spinocerebellar Ataxia Type 6 21 3.8 Spinocerebellar Ataxia Type 7 22 3.9 Spinocerebellar Ataxia Type 17 25 3.10 Role of Aggregation in Polyglutamine Disease Pathogenesis 25 3.11 Protein Context 29 3.12 Transcriptional Dysregulation 30 3.13 Proteolytic Cleavage 30 4 Type 2: the Loss-of-function Repeat Diseases 33 4.1 Fragile X Syndrome 33 Encyclopedia of Molecular Cell Biology and Molecular Medicine, 2nd Edition. Volume 15 Edited by Robert A. Meyers. Copyright 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-30652-8 2 Triplet Repeat Diseases 4.2 Fragile XE Mental Retardation 34 4.3 Friedreich’s Ataxia 36 4.4 Progressive Myoclonus Epilepsy Type 1 39 5 Type 3: the RNA Gain-of-function Repeat Diseases
    [Show full text]
  • REVIEW ARTICLE Genetic Disorders of the Skeleton: a Developmental Approach
    Am. J. Hum. Genet. 73:447–474, 2003 REVIEW ARTICLE Genetic Disorders of the Skeleton: A Developmental Approach Uwe Kornak and Stefan Mundlos Institute for Medical Genetics, Charite´ University Hospital, Campus Virchow, Berlin Although disorders of the skeleton are individually rare, they are of clinical relevance because of their overall frequency. Many attempts have been made in the past to identify disease groups in order to facilitate diagnosis and to draw conclusions about possible underlying pathomechanisms. Traditionally, skeletal disorders have been subdivided into dysostoses, defined as malformations of individual bones or groups of bones, and osteochondro- dysplasias, defined as developmental disorders of chondro-osseous tissue. In light of the recent advances in molecular genetics, however, many phenotypically similar skeletal diseases comprising the classical categories turned out not to be based on defects in common genes or physiological pathways. In this article, we present a classification based on a combination of molecular pathology and embryology, taking into account the importance of development for the understanding of bone diseases. Introduction grouping of conditions that have a common molecular origin but that have little in common clinically. For ex- Genetic disorders affecting the skeleton comprise a large ample, mutations in COL2A1 can result in such diverse group of clinically distinct and genetically heterogeneous conditions as lethal achondrogenesis type II and Stickler conditions. Clinical manifestations range from neonatal dysplasia, which is characterized by moderate growth lethality to only mild growth retardation. Although they retardation, arthropathy, and eye disease. It is now be- are individually rare, disorders of the skeleton are of coming increasingly clear that several distinct classifi- clinical relevance because of their overall frequency.
    [Show full text]