DOCSLIB.ORG

Clinical and Genetic Studies of Three Inherited Skeletal Disorders

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Clinical and Genetic Studies of Three Inherited Skeletal Disorders UMEÅ UNIVERSITY MEDICAL DISSERTATIONS New Series No. 1259 ISSN 0346-6612 ISBN 978-91-7264-753-4 Clinical and Genetic Studies of Three Inherited Skeletal Disorders Eva-Lena Stattin From the Department of Medical Biosciences Medical and Clinical Genetics Umeå University SE-901 85 Umeå Sweden 2009 Copyright© 2009 by Eva-Lena Stattin New Series No. 1259 ISBN: 978-91-7264-753-4 ISSN: 0346-6612 Cover: Pedigree, familial osteochondritis dissecans Printed by: Hemströms tryckeri, Härnösand, Sweden 2009 To Pär, Kalle and Oskar 3 Contents CONTENTS .......................................................................................................................4 PUBLICATIONS...............................................................................................................6 THESIS AT A GLANCE ..................................................................................................7 ABSTRACT .......................................................................................................................8 ABBREVIATIONS............................................................................................................9 M0B EDICAL GENETICS ............................................................................................ 11 Human28B genome................................................................................................................. 11 DNA29B structure...................................................................................................................11 Characteristics30B of Mendelian inheritance.......................................................................... 11 Inter31B individual variations................................................................................................. 12 INTRODUCTION ...........................................................................................................14 The15B Skeleton................................................................................................ 14 Extracellula16B r matrix ...................................................................................... 14 Cartila17B ge....................................................................................................... 15 C1B OMPONENTS OF THE EXTRACELLULAR MATRIX NETWORK.................................... 16 The18B large aggregating Proteoglycans.......................................................... 16 ACAN-gene19B and Aggrecan .......................................................................... 16 Molecular32B gene structure, organization and function........................................................ 16 C2B HONDRODYSPLASIAS DUE TO AGGRECAN DEFECTS............................................. 18 C3B HONDRODYSPLASIAS DUE TO AGGRECAN DEFECTS - ANIMAL MODELS ................. 19 Cartilage3B matrix deficiency............................................................................................... 19 Cartilage34B matrix deficiency-Bc......................................................................................... 19 Nanomelia......................................................................................................................35B ... 19 Bulldog36B dwarfism ............................................................................................................. 19 C4B HONDRODYSPLASIAS DUE TO AGGRECAN DEFECTS – HUMAN DISORDERS............ 20 Spondyloepiphyseal37B dysplasia type Kimberley (SEDK)................................................... 20 Spondyloepimetaphyseal38B dysplasia (SEMD-aggrecan-type) ............................................ 20 Familial39B osteochondritis dissecans.................................................................................... 20 Disorders associated with defective sulfation of proteoglycans .................. 21 Degenerative20B diseases involving aggrecan ................................................. 21 VNTR-region40B of the ACAN-gene and OA ....................................................................... 21 Age-related41B changes of aggrecan...................................................................................... 22 C5B OMPONENTS OF THE EXTRACELLULAR MATRIX NETWORK.................................... 22 The42B Collagens...................................................................................................................22 CHONDRODYSPLASIA DUE TO DEFECTS IN ECM-PROTEINS ................................... 23 Multiple43B epiphyseal dysplasia........................................................................................... 23 SKELETONENESIS ............................................................................................... 23 The2B Indian Hedgehog (IHH)-gene; an important gene for skeletal development................................................................................................. 24 Brachydactyly4B type A1 ..................................................................................................... 25 AIMS OF THE THESIS .................................................................................................26 4 METHODOLOGY ..........................................................................................................27 Ethics.........................................................................................................................45B ....... 27 Introduction23B to field work .............................................................................. 27 Collecting46B clinical material............................................................................................... 27 Evaluation47B of suspected skeletal dysplasias...................................................................... 27 Field24B work..................................................................................................... 27 Study48B I and II (Familial OCD).......................................................................................... 27 Study49B III (MED) ............................................................................................................... 28 Study50B IV (BDA1).............................................................................................................. 28 Methods25B ....................................................................................................... 29 Statistical51B analysis............................................................................................................. 29 Linkage52B analysis ............................................................................................................... 29 Molecular26B genetics methods ........................................................................ 29 DNA53B extraction................................................................................................................. 29 PCR .................................................................................................................................. 29 Genome-wide54B scan ........................................................................................................... 30 Sequencing/Candidate5B gene analysis ................................................................................ 30 Interpretation56B of identified variations ............................................................................... 31 DHPLC..........................................................................................................................57B ... 31 Restriction58B endonuclease digestion of the PCR product ................................................... 32 Protein59B interaction analysis............................................................................................... 32 Mass60B spectrometry............................................................................................................ 33 RESULTS AND DISCUSSION ......................................................................................34 P7B APER I ............................................................................................................. 34 P8B APER II ............................................................................................................ 36 P9B APER III ........................................................................................................... 39 P10B APER IV ........................................................................................................... 41 Concluding27B remarks and future perspectives .............................................. 43 POPULÄRVETENSKAPLIG SAMMANFATTNING PÅ SVENSKA ......................44 I1B NTRODUKTION ................................................................................................... 44 M12B ANUSKRIPT I & II .............................................................................................. 44 M13B ANUSKRIPT III .................................................................................................. 45 M14B ANUSKRIPT IV.................................................................................................. 46 ACKNOWLEDGEMENTS ............................................................................................47 REFERENCES ................................................................................................................49 5 Publications This thesis is based on the following original publications, which will be referred to by their roman numerals:
Load more

Recommended publications
  • (AMIC) Compared to Microfractures for Chondral Defects of the Talar Shoulder: a Five-Year Follow-Up Prospective Cohort Study
    life Communication Autologous Matrix Induced Chondrogenesis (AMIC) Compared to Microfractures for Chondral Defects of the Talar Shoulder: A Five-Year Follow-Up Prospective Cohort Study Filippo Migliorini 1 , Jörg Eschweiler 1, Nicola Maffulli 2,3,4,5,* , Hanno Schenker 1, Arne Driessen 1 , Björn Rath 1,6 and Markus Tingart 1 1 Department of Orthopedics and Trauma Surgery, University Clinic Aachen, RWTH Aachen University Clinic, 52064 Aachen, Germany; [email protected] (F.M.); [email protected] (J.E.); [email protected] (H.S.); [email protected] (A.D.); [email protected] (B.R.); [email protected] (M.T.) 2 School of Pharmacy and Bioengineering, Keele University School of Medicine, Staffordshire ST4 7QB, UK 3 Barts and the London School of Medicine and Dentistry, London E1 2AD, UK 4 Centre for Sports and Exercise Medicine, Queen Mary University of London, Mile End Hospital, London E1 4DG, UK 5 Department of Orthopedics, Klinikum Wels-Grieskirchen, A-4600 Wels, Austria 6 Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy * Correspondence: [email protected] Abstract: Introduction: Many procedures are available to manage cartilage defects of the talus, Citation: Migliorini, F.; Eschweiler, J.; including microfracturing (MFx) and Autologous Matrix Induced Chondrogenesis (AMIC). Whether Maffulli, N.; Schenker, H.; Driessen, AMIC or MFx are equivalent for borderline sized defects of the talar shoulder is unclear. Thus, the A.; Rath, B.; Tingart, M. Autologous present study compared the efficacy of primary isolated AMIC versus MFx for borderline sized Matrix Induced Chondrogenesis focal unipolar chondral defects of the talar shoulder at midterm follow-up.
    [Show full text]
  • Comparative Anatomy of the Lower Respiratory Tract of the Gray Short-Tailed Opossum (Monodelphis Domestica) and North American Opossum (Didelphis Virginiana)
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 12-2001 Comparative Anatomy of the Lower Respiratory Tract of the Gray Short-tailed Opossum (Monodelphis domestica) and North American Opossum (Didelphis virginiana) Lee Anne Cope University of Tennessee - Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Animal Sciences Commons Recommended Citation Cope, Lee Anne, "Comparative Anatomy of the Lower Respiratory Tract of the Gray Short-tailed Opossum (Monodelphis domestica) and North American Opossum (Didelphis virginiana). " PhD diss., University of Tennessee, 2001. https://trace.tennessee.edu/utk_graddiss/2046 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Lee Anne Cope entitled "Comparative Anatomy of the Lower Respiratory Tract of the Gray Short-tailed Opossum (Monodelphis domestica) and North American Opossum (Didelphis virginiana)." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Animal Science. Robert W. Henry, Major Professor We have read this dissertation and recommend its acceptance: Dr. R.B. Reed, Dr. C. Mendis-Handagama, Dr. J. Schumacher, Dr. S.E. Orosz Accepted for the Council: Carolyn R.
    [Show full text]
  • Autologous Matrix-Induced Chondrogenesis and Generational Development of Autologous Chondrocyte Implantation
    Autologous Matrix-Induced Chondrogenesis and Generational Development of Autologous Chondrocyte Implantation Hajo Thermann, MD, PhD,* Christoph Becher, MD,† Francesca Vannini, MD, PhD,‡ and Sandro Giannini, MD‡ The treatment of osteochondral defects of the talus is still controversial. Matrix-guided treatment options for covering of the defect with a scaffold have gained increasing popularity. Cellular-based autologous chondrocyte implantation (ACI) has undergone a generational development overcoming the surgical drawbacks related to the use of the periosteal flap over time. As ACI is associated with high costs and limited in availability, autologous matrix-induced chondrogenesis, a single-step procedure combining microfracturing of the subchondral bone to release bone marrow mesenchymal stem cells in combination with the coverage of an acellular matrix, has gained increasing popularity. The purposes of this report are to present the arthroscopic approach of the matrix-guided autologous matrix-induced chondrogenesis technique and generational development of ACI in the treatment of chondral and osteochon- dral defects of the talus. Oper Tech Orthop 24:210-215 C 2014 Elsevier Inc. All rights reserved. KEYWORDS cartilage, defect, ankle, talus, AMIC, ACI Introduction Cartilage repair may be obtained by cartilage replacement: (OATS, mosaicplasty) or with techniques aimed to generate a hondral and osteochondral lesions are defects of the newly formed cartilage such as microfracture or autologous Ccartilaginous surface and underlying subchondral bone of chondrocyte implantation (ACI).9-17 the talar dome. These defects are often caused by a single or Arthroscopic debridement and bone marrow stimulation multiple traumatic events, mostly inversion or eversion ankle using the microfracture technique has proven to be an 1,2 sprains in young, active patients.
    [Show full text]
  • Inheritance of Multiple Epiphyseal Dysplasia, Tarda
    Inheritance of Multiple Epiphyseal Dysplasia, Tarda RICHARD C. JUBERG1 AND JOHN F. HOLT2 Multiple epiphyseal dysplasia, tarda, a modeling error of the epiphyses, is charac- terized by shortness of stature and micromelia, particularly stubby hands (Rubin, 1964). A patient with this trait generally shows satisfactory development, adequate muscle mass, and normal intelligence. As a rule, there are few complaints of joint discomfort during childhood. Eventually, however, problems arise from joint motion, which lead to difficulty in walking because of pain in the hips, knees, or ankles. De- formities may result. On the other hand, the defect may not be recognized until the patient presents manifestations of degenerative arthritis at an unusually early age. The classification of epiphyseal modeling errors by Rubin (1964) contains six different entities. Spondyloepiphyseal dysplasia, congenita (Morquio's disease) is characterized by irregularity of epiphyses and vertebrae. It is an abnormality of mucopolysaccharide metabolism, and it is transmitted as an autosomal recessive. Multiple epiphyseal dysplasia, congenita (stippled epiphyses) is characterized by stippled or punctate epiphyses, and it too is transmitted as an autosomal recessive. Epiphyseal retardation, which occurs in cretinism (hypothyroidism), may result from any of several different metabolic errors which appear to be transmitted as autosomal recessives (Stanbury, 1966). Diastrophic dwarfism results in delayed appearance of epiphyses and joint luxations, and this, too, apparently is transmitted as an autosomal recessive. Multiple epiphyseal dysplasia, tarda, which is also known in the literature as epi- physeal dysplasia multiplex, must be differentiated from spondyloepiphyseal dys- plasia, tarda. As the name implies, one difference is in the extent and severity of spinal involvement as well as in the changes in the epiphyses of the long tubular bones.
    [Show full text]
  • 16 Cartilage
    Cartilage Cartilage serves as a rigid yet lightweight and flexible supporting tissue. It forms the framework for the respiratory passages to prevent their collapse, provides smooth "bearings" at joints, and forms a cushion between the vertebrae, acting as a shock absorber for the spine. Cartilage is important in determining the size and shape of bones and provides the growing areas in many bones. Its capacity for rapid growth while maintaining stiffness makes cartilage suitable for the embryonic skeleton. About 75% of the water in cartilage is bound to proteoglycans, and these compounds are important in the transport of fluids, electrolytes, and nutrients throughout the cartilage matrix. Although adapted to provide support, cartilage contains only the usual elements of connective tissue cells, fibers, and ground substance. It is the ground substance that gives cartilage its firm consistency and ability to withstand compression and shearing forces. Collagen and elastic fibers embedded in the ground substance impart tensile strength and elasticity. Together, the fibers and ground substance form the matrix of cartilage. Cartilage differs from other connective tissues in that it lacks nerves, blood and lymphatic vessels and is nourished entirely by diffusion of materials from blood vessels in adjacent tissues. Although relatively rigid, the cartilage matrix has high water content and is freely permeable, even to fairly large particles. Classification of cartilage into hyaline, elastic, and fibrous types is based on differences in the abundance and type of fibers in the matrix. Hyaline Cartilage Hyaline cartilage is the most common type of cartilage and forms the costal cartilages, articular cartilages of joints, and cartilages of the nose, larynx, trachea, and bronchi.
    [Show full text]
  • Adult Chondrogenesis and Spontaneous Cartilage Repair in the Skate, Leucoraja Erinacea Aleksandra Marconi1, Amy Hancock-Ronemus2,3, J Andrew Gillis1,3*
    RESEARCH ARTICLE Adult chondrogenesis and spontaneous cartilage repair in the skate, Leucoraja erinacea Aleksandra Marconi1, Amy Hancock-Ronemus2,3, J Andrew Gillis1,3* 1Department of Zoology, University of Cambridge, Cambridge, United Kingdom; 2Charles River Laboratories, Wilmington, Massachusetts, United States; 3Marine Biological Laboratory, Woods Hole, Massachusetts, United States Abstract Mammalian articular cartilage is an avascular tissue with poor capacity for spontaneous repair. Here, we show that embryonic development of cartilage in the skate (Leucoraja erinacea) mirrors that of mammals, with developing chondrocytes co-expressing genes encoding the transcription factors Sox5, Sox6 and Sox9. However, in skate, transcriptional features of developing cartilage persist into adulthood, both in peripheral chondrocytes and in cells of the fibrous perichondrium that ensheaths the skeleton. Using pulse-chase label retention experiments and multiplexed in situ hybridization, we identify a population of cycling Sox5/6/9+ perichondral progenitor cells that generate new cartilage during adult growth, and we show that persistence of chondrogenesis in adult skates correlates with ability to spontaneously repair cartilage injuries. Skates therefore offer a unique model for adult chondrogenesis and cartilage repair and may serve as inspiration for novel cell-based therapies for skeletal pathologies, such as osteoarthritis. Introduction Hyaline cartilage is a skeletal tissue that consists of a single cell type (the chondrocyte) embedded *For correspondence: [email protected] within a homogeneous, collagenous extracellular matrix (reviewed in Gillis, 2018). In mammals, hya- line cartilage is predominantly an embryonic tissue, making up the anlage of the axial (chondrocra- Competing interests: The nial, vertebral and rib) and appendicular (limb) endoskeleton. The vast majority of mammalian authors declare that no hyaline cartilage is replaced by bone during the process of endochondral ossification, with cartilage competing interests exist.
    [Show full text]
  • Nomina Histologica Veterinaria, First Edition
    NOMINA HISTOLOGICA VETERINARIA Submitted by the International Committee on Veterinary Histological Nomenclature (ICVHN) to the World Association of Veterinary Anatomists Published on the website of the World Association of Veterinary Anatomists www.wava-amav.org 2017 CONTENTS Introduction i Principles of term construction in N.H.V. iii Cytologia – Cytology 1 Textus epithelialis – Epithelial tissue 10 Textus connectivus – Connective tissue 13 Sanguis et Lympha – Blood and Lymph 17 Textus muscularis – Muscle tissue 19 Textus nervosus – Nerve tissue 20 Splanchnologia – Viscera 23 Systema digestorium – Digestive system 24 Systema respiratorium – Respiratory system 32 Systema urinarium – Urinary system 35 Organa genitalia masculina – Male genital system 38 Organa genitalia feminina – Female genital system 42 Systema endocrinum – Endocrine system 45 Systema cardiovasculare et lymphaticum [Angiologia] – Cardiovascular and lymphatic system 47 Systema nervosum – Nervous system 52 Receptores sensorii et Organa sensuum – Sensory receptors and Sense organs 58 Integumentum – Integument 64 INTRODUCTION The preparations leading to the publication of the present first edition of the Nomina Histologica Veterinaria has a long history spanning more than 50 years. Under the auspices of the World Association of Veterinary Anatomists (W.A.V.A.), the International Committee on Veterinary Anatomical Nomenclature (I.C.V.A.N.) appointed in Giessen, 1965, a Subcommittee on Histology and Embryology which started a working relation with the Subcommittee on Histology of the former International Anatomical Nomenclature Committee. In Mexico City, 1971, this Subcommittee presented a document entitled Nomina Histologica Veterinaria: A Working Draft as a basis for the continued work of the newly-appointed Subcommittee on Histological Nomenclature. This resulted in the editing of the Nomina Histologica Veterinaria: A Working Draft II (Toulouse, 1974), followed by preparations for publication of a Nomina Histologica Veterinaria.
    [Show full text]
  • Congenital Abnormalities Reported in Pelger-Huët Homozygosity As Compared to Greenberg/HEM Dysplasia
    937 LETTER TO JMG J Med Genet: first published as 10.1136/jmg.40.12.937 on 18 December 2003. Downloaded from Congenital abnormalities reported in Pelger-Hue¨t homozygosity as compared to Greenberg/HEM dysplasia: highly variable expression of allelic phenotypes J C Oosterwijk, S Mansour, G van Noort, H R Waterham, C M Hall, R C M Hennekam ............................................................................................................................... J Med Genet 2003;40:937–941 n 1928 the Dutch physician Pelger described two patients Key points with a morphological abnormality of leukocytes that Iconsisted of hypolobulation of the nuclei: there were two lobes instead of the usual five or more and the chromatin N Pelger-Hue¨t anomaly (PHA) is a benign, autosomal structure was coarse and denser.1 This was subsequently dominant haematological trait characterised by hypo- shown to be a genetic trait by paediatrician Hue¨t.2 In the lobulation of granulocyte nuclei. PHA homozygosity, following years many families with Pelger-Hue¨t anomaly however, is associated with skeletal abnormalities and (PHA) from different countries were reported and autosomal early lethality on the basis of animal studies and case dominant inheritance was firmly established.3 Bilobulated reports. In 2002 PHA was found to be due to PHA nuclei (‘‘spectacle’’ or ‘‘pince-nez’’ cells) can also be a heterozygous mutations in the lamin B receptor gene transient symptom in the presence of underlying disease (— (LBR), and a homozygous LBR mutation was detected in for example, infection, myeloid leukaemia or medication) as a boy with mild congenital abnormalities. Homozygous part of a ‘‘shift to the left’’ (pseudo PHA), but constitutional mutations in Lbr cause the ic/ic phenotype in mice.
    [Show full text]
  • Blueprint Genetics Comprehensive Skeletal Dysplasias and Disorders
    Comprehensive Skeletal Dysplasias and Disorders Panel Test code: MA3301 Is a 251 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of disorders involving the skeletal system. About Comprehensive Skeletal Dysplasias and Disorders This panel covers a broad spectrum of skeletal disorders including common and rare skeletal dysplasias (eg. achondroplasia, COL2A1 related dysplasias, diastrophic dysplasia, various types of spondylo-metaphyseal dysplasias), various ciliopathies with skeletal involvement (eg. short rib-polydactylies, asphyxiating thoracic dysplasia dysplasias and Ellis-van Creveld syndrome), various subtypes of osteogenesis imperfecta, campomelic dysplasia, slender bone dysplasias, dysplasias with multiple joint dislocations, chondrodysplasia punctata group of disorders, neonatal osteosclerotic dysplasias, osteopetrosis and related disorders, abnormal mineralization group of disorders (eg hypopohosphatasia), osteolysis group of disorders, disorders with disorganized development of skeletal components, overgrowth syndromes with skeletal involvement, craniosynostosis syndromes, dysostoses with predominant craniofacial involvement, dysostoses with predominant vertebral involvement, patellar dysostoses, brachydactylies, some disorders with limb hypoplasia-reduction defects, ectrodactyly with and without other manifestations, polydactyly-syndactyly-triphalangism group of disorders, and disorders with defects in joint formation and synostoses. Availability 4 weeks Gene Set Description
    [Show full text]
  • The Osteopetrotic Mutation Toothless (Tl) Is a Loss-Of-Function Frameshift Mutation in the Rat Csf1 Gene: Evidence of a Crucial
    The osteopetrotic mutation toothless (tl)isa loss-of-function frameshift mutation in the rat Csf1 gene: Evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification Liesbeth Van Wesenbeeck*, Paul R. Odgren†, Carole A. MacKay†, Marina D’Angelo‡§, Fayez F. Safadi‡, Steven N. Popoff‡, Wim Van Hul*, and Sandy C. Marks, Jr.†¶ *Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, Antwerp B-2610, Belgium; †Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue, North Worcester, MA 01655; and ‡Department of Anatomy and Cell Biology, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140 Edited by Elizabeth D. Hay, Harvard Medical School, Boston, MA, and approved July 30, 2002 (received for review June 3, 2002) The toothless (tl) mutation in the rat is a naturally occurring, dritic cells, and formation of osteoclasts (refs. 9–12; reviewed in autosomal recessive mutation resulting in a profound deficiency of ref. 13). The transcription factor PU.1 functions in osteoclast bone-resorbing osteoclasts and peritoneal macrophages. The fail- differentiation and activation and in myeloid cells and B lym- ure to resorb bone produces severe, unrelenting osteopetrosis, phocytes (14); and NF-␬B, originally described as regulating with a highly sclerotic skeleton, lack of marrow spaces, failure of transcription of Ig light chain genes, is likewise necessary for tooth eruption, and other pathologies. Injections of CSF-1 improve osteoclastogenesis (15). some, but not all, of these. In this report we have used polymor- Phenotypes of osteopetrotic mutations vary widely, depending phism mapping, sequencing, and expression studies to identify the on where bone resorption is intercepted.
    [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]
  • Endochondral Bone Formation in Toothless (Osteopetrotic) Rats: Failures of Chondrocyte Patterning and Type X Collagen Expression
    University of Massachusetts Medical School eScholarship@UMMS Open Access Articles Open Access Publications by UMMS Authors 2000-04-01 Endochondral bone formation in toothless (osteopetrotic) rats: failures of chondrocyte patterning and type X collagen expression Sandy C. Marks Jr. University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Cell Biology Commons, and the Developmental Biology Commons Repository Citation Marks SC, Lundmark C, Christersson C, Wurtz T, Odgren PR, Seifert MF, MacKay CA, Mason-Savas A, Popoff SN. (2000). Endochondral bone formation in toothless (osteopetrotic) rats: failures of chondrocyte patterning and type X collagen expression. Open Access Articles. Retrieved from https://escholarship.umassmed.edu/oapubs/633 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Articles by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Int. J. Dev. Biol. 44: 309-316 (2000) Chondrocytes, collagen X and mineralization 309 Original Article Endochondral bone formation in toothless (osteopetrotic) rats: failures of chondrocyte patterning and type X collagen expression SANDY C. MARKS, JR.1,2, CARIN LUNDMARK2, CECILIA CHRISTERSSON2, TILMANN WURTZ2, PAUL R. ODGREN1, MARK F. SEIFERT 3, CAROLE A. MACKAY1, APRIL MASON-SAVAS1 and STEVEN N. POPOFF4 1Department of Cell Biology, University of Massachusetts Medical Center, Worcester, MA, USA, 2Center for Oral Biology, Karolinska Institute, Huddinge, Sweden, 3Department of Anatomy, Indiana University School of Medicine, Indianapolis, IN and 4Department of Anatomy, Temple University School of Medicine, Philadelphia, PA, USA ABSTRACT The pacemaker of endochondral bone growth is cell division and hypertrophy of chondrocytes.
    [Show full text]