Dysmorphology

Introduction

The Dysmorphology, Bone and Cartilage Screen of the GMC contributes the phenotyping for bone and cartilage related phenotypes as well as for morphological abnormalities. The aim of the screen is to establish mouse models for human skeletal diseases like osteoporosis, scoliosis, limb defects, osteogenesis imperfecta or osteoarthritis.

Primary Screening

For the primary screen, we cover a broad spectrum of parameters of bone development, bone metabolism and homeostasis. We have implemented an experimental set up, which enables us to perform high throughput non-invasive first-line phenotyping for bone and cartilage abnormalities. In addition, we developed a protocol (54 parameters) for a quick anatomical observation of animals, which is able to detect and evaluate malformations and malfunctions of the different organ systems.

Analysis

1. Dysmorphological Analysis:

  • Quick and easy whole body check up for anatomical abnormalities and malfunctions in different organ systems.

2. X-ray Analysis:

  • Within a few seconds the whole mouse skeleton can be visualised, X-rays of special parts can be obtained in higher magnification.
  • Judgments of the appearance and presence of all bones and joints can be made.
  • Information about developmental disorders and to a minor extent bone metabolic disorders.

    3. Bone densitometry:

    • Measurement of bone mineral density and body composition rapidly and quantitatively.
    •  Information about bone mineralization and homeostasis defects (e.g. osteoporosis, osteogenesis imperfecta).

    Secondary Screen

    In secondary tests, we evaluate mutants with altered parameters in the primary screen for the use as model systems for human bone related diseases like scoliosis, limb defects, osteoporosis, osteogenesis imperfecta or osteoarthritis by more detailed phenotypic characterisation.

    1. pQCT (peripheral quantitative computed tomography):

    •  Enables volumetric bone density measurements in g/cm3 of the appendicular skeleton and tail vertebra (in vivo).
    • Separates cortical and trabecular bone compartements (BMD, BMC, bone area).


    2. µCT (micro computed tomography):

    • Helps to obtain a better view of the abnormality (in vivo and in vitro).
    • In vivo imaging with a resolution down to 9 microns.
    • In vitro resolution down to 0,7 microns.

    3. Markers of bone turnover/metabolism and hormonal regulation:

    •  The purpose is to identify mutants of systemic metabolic bone diseases quickly and non-invasively.
    • Measurement of bone formation, bone resorption, and hormonal markers in serum, plasma, and cell culture supernatants.


    4. Mechanical bending: three-point bend test:

    • Measurement of plastic and elastic stability or fracture parameters of bones.

    5. Skeleton preparation:

    • Staining with alcian blue (cartilage) and alizarin red (bone)

    We are using standardised and validated protocols established by the EUMORPHIAConsortium (http://www.eumorphia.org/).  With our work, we contributed to the development of bone phenotyping protocols. Individual standard operating procedures (SOPs) for phenotyping are available on the European Mouse Phenotyping Resource of Standardised Screens (EMPReSS): http://www.empress.har.mrc.ac.uk/


    References (selected publications)

    1. Fuchs H, Gailus-Durner V, Adler T, Aguilar-Pimentel JA, Becker L, Calzada-Wack J, Da Silva-Buttkus P, Neff F, Götz A, Hans W, Hölter SM, Horsch M, Kastenmüller G, Kemter E, Lengger C, Maier H, Matloka M, Möller G, Naton B, Prehn C, Puk O, Rácz I, Rathkolb B, Römisch-Margl W, Rozman J, Wang-Sattler R, Schrewe A, Stöger C, Tost M, Adamski J, Aigner B, Beckers J, Behrendt H, Busch DH, Esposito I, Graw J, Illig T, Ivandic B, Klingenspor M, Klopstock T, Kremmer E, Mempel M, Neschen S, Ollert M, Schulz H, Suhre K, Wolf E, Wurst W, Zimmer A, Hrabě de Angelis M.: Mouse phenotyping. Methods. 2011; Feb;53(2):120-135.
    2. Abe K, Fuchs H, Boersma A, Hans W, Yu P, Kalaydjiev S, Klaften M, Adler T, Calzada-Wack J, Mossbrugger I, Rathkolb B, Rozman J, Prehn C, Maraslioglu M, Kametani Y, Shimada S, Adamski J, Busch DH, Esposito I, Klingenspor M, Wolf E, Wurst W, Gailus-Durner V, Katan M, Marschall S, Soewarto D, Wagner S, de Angelis MH.: A novel ENU-induced mutation in Phospholipase C gamma 2 causes inflammatory arthritis, metabolic defects, and in vitro male infertility in the mouse. Arthritis Rheum.-US. 2011; 63 (5): 1301–1311.
    3. Lisse TS, Thiele F, Fuchs H, Hans W, Przemeck GK, Abe K, Rathkolb B, Quintanilla-Martinez L, Hoelzlwimmer G, Helfrich M, Wolf E, Ralston SH, Hrabé de Angelis M.: ER Stress-Mediated Apoptosis in a New Mouse Model of Osteogenesis imperfecta. PLoS Genet. 2008 4(2):e7
    4. Fuchs, H., Lisse, T., Hans, W., Abe, K., Thiele, F., Gailus-Durner, V., Hrabé de Angelis, M.: Phenotypic characterization of mouse models for bone-related diseases in the German Mouse Clinic. J. Musculoskelet. Neuronal. Interact. 2008 Jan-Mar;8(1):13-4.
    5. Fuchs H, Lisse T, Abe K, Hrabé de Angelis M. Screening for bone and cartilage phenotypes in mice. In: Standards of Mouse Model Phenotyping. Eds.: Hrabé de Angelis M., Chambon P. and Browns S. Wiley-VCH Verlag GmbH, Weinheim (Germany). 2006; pp. 35-86.
    6. Fuchs H, Schughart K, Wolf E, Balling R, Hrabé de Angelis M. Screening for dysmorphological abnormalities - a powerful tool to isolate new mouse mutants. Mamm Genome. 2000 Jul;11(7):528-30.
    7. Olszewski PK, Rozman J, Jacobsson JA, Rathkolb B, Strömberg S, Hans W, Klockars A, Alsiö J, Risérus U, Becker L, Hölter SM, Elvert R, Erhardt N, Gailus-Durner V, Fuchs H, Fredriksson R, Wolf E, Klopstock T, Wurst W, Levine AS, Marcus C, Hrabě de Angelis M, Klingenspor M, Schiöth HB, Kilimann MW: Neurobeachin, a regulator of synaptic protein targeting, is associated with body fat mass and feeding behavior in mice and body-mass index in humans. PLoS Genet 2012; 8(3), e1002568 DOI:10.1371/journal.pgen.1002568
    8. Horsch M, Seeburg PH, Adler T, Aguilar-Pimentel JA, Becker L, Calzada-Wack J, Garrett L, Götz A, Hans W, Higuchi M, Hölter SM, Naton B, Prehn C, Puk O, Rácz I, Rathkolb B, Rozman J, Schrewe A, Adamski J, Busch DH, Esposito I, Graw J, Ivandic B, Klingenspor M, Klopstock T, Mempel M, Ollert M, Schulz H, Wolf E, Wurst W, Zimmer A, Gailus-Durner V, Fuchs H, Hrabé de Angelis M, Beckers J. Requirement of the RNA-editing enzyme ADAR2 for normal physiology in mice. J Biol Chem. 2011; 286(21):18614-22.
    9. Saarikangas J, Mattila PK, Varjosalo M, Bovellan M, Hakanen J, Calzada-Wack J, Tost M, Jennen L, Rathkolb B, Hans W, Horsch M, Hyvönen ME, Perälä N, Fuchs H, Gailus-Durner V, Esposito I, Wolf E, Hrabé de Angelis M, Frilander MJ, Savilahti H, Sariola H, Sainio K, Lehtonen S, Taipale J, Salminen M, Lappalainen P.:Missing-in-metastasis MIM/MTSS1 promotes actin assembly at intercellular junctions and is required for integrity of kidney epithelia. J Cell Sci. 2011; 124, 1245-1255.
    10. Kemter E, Rathkolb B, Bankir L, Schrewe A, Hans W, Landbrecht C, Klaften M, Ivandic B, Fuchs H, Gailus-Durner V, Hrabé de Angelis M, Wolf E, Wanke R, Aigner B.: Mutation of the Na(+)-K(+)-2Cl(-) cotransporter NKCC2 in mice is associated with severe polyuria and a urea-selective concentrating defect without hyperreninemia. Am J Physiol Renal Physiol. 2010; 298:F1405-F1415
    11. Kemter E, Rathkolb B, Rozman J, Hans W, Schrewe A, Landbrecht C, Klaften M, Ivandic B, Fuchs H, Gailus-Durner V, Klingenspor M, Hrabé de Angelis M, Wolf E, Wanke R, Aigner B. Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism. Am J Physiol Renal Physiol. 2009 Nov;297(5):F1391-8.
    12. Vreugde S, Erven A, Kros CJ, Marcotti W, Fuchs H, Kurima K, Wilcox ER, Friedman TB, Griffith AJ, Balling R, Hrabé de Angelis M, Avraham KB, Steel KP.
      Beethoven, a mouse model for dominant, progressive hearing loss DFNA36. Nat Genet. 2002 Mar;30(3):257-8. Epub 2002 Feb 19.
    13. Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, Ahmad-Annuar A, Bowen S, Lalli G, Witherden AS, Hummerich H, Nicholson S, Morgan PJ, Oozageer R, Priestley JV, Averill S, King VR, Ball S, Peters J, Toda T, Yamamoto A, Hiraoka Y, Augustin M, Korthaus D, Wattler S, Wabnitz P, Dickneite C, Lampel S, Boehme F, Peraus G, Popp A, Rudelius M, Schlegel J, Fuchs H, Hrabé de Angelis M, Schiavo G, Shima DT, Russ AP, Stumm G, Martin JE, Fisher EM.
      Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science. 2003 May 2;300(5620):808-12.

    Head

    Dr. Helmut Fuchs    
    phone : +49 (089) 3187-3151
    fax:      +49 (089) 3187-3500
    e-mail:

    Prof. Dr. Martin Hrabé de Angelis    
    phone : +49 (089) 3187-3302
    fax:      +49 (089) 3187-3500
    e-mail: