Bone, Cartilage and Dysmorphology
Overview
The bone, cartilage and dysmorphology subgroup of the Institute of Experimental Genetics focuses on the detection and characterisation of animal model systems for human inherited diseases in terms of bone and cartilage development and homeostasis as well as morphological abnormalities in different organ systems. The Dysmorphology, bone and cartilage part of the Institute contributes to the ENU-Mouse-Mutagenesis-Screen and to the German Mouse Clinic (GMC). Bone and cartilage mutants derived from these platforms are characterised in detail in our lab. Mutants with other interesting phenotypes are analysed in collaboration with specialized labs in the corresponding fields of research. We are involved in European funded projects (Eumorphia , Anabonos) and a German-Israelian fund.
Goals
Our aim is to provide new animal model systems for human inherited diseases of different organ systems. Our special focus is on bone and cartilage development and homeostasis, like osteoporosis, osteoarthritis or abnormalities in limb development.
Experimental strategy and technology
We use two large-scale projects, the German Mouse Clinic and the ENU-mutagenesis screen, as platforms for the development of new mouse mutants and the evaluation of mouse mutant lines as potential model system for human diseases. Selected mutant lines then undergo detailed characterisation.
We are equipped with machines that are suitable for the high throughput non-invasive first-line phenotyping of mice for bone and cartilage abnormalities, like DEXA, (dual energy X-ray absorption), X-ray imaging, micro computer tomography, or blood analysers. In addition we have developed a protocol (49 parameters) for a quick anatomical observation of animals, which is able to detect and evaluate malformations and malfunction of the different organ systems.
Main results
In our ENU mutagenesis screen (Hrabe de Angelis et al. 2000), we established 285 dysmorphology mutant lines since the beginning of the project (Fuchs et al. 2000).
Table: Established Mutant Mouse Lines
|
| Dominant | Recessive |
|---|---|---|
| Skeleton | 105 | 17 |
| Body size and weight | 15 | 8 |
| Teeth | 4 | 1 |
| Deafness | 15 | 3 |
| Eyes | 21 | 0 |
| Skin and hair | 32 | 8 |
| Behaviour | 48 | 9 |
| Coat | 58 | 6 |
| ∑ | 298 | 52 |
Here a list of dysmorphology mutants can be found.
In the German Mouse Clinic (GMC) we have analysed four inbred mouse strain, two hybrid strains and 22 mutant lines. In seventeen out of the 22 mutant lines we could detect significant differences between mutants and controls. Seven mutant lines were selected for more detailed analysis of bone structure and metabolism.
Currently we work on three model systems for osteoarthritis, two mutant lines for osteoporosis, one model for brittle bone disease and a series of mutants with malformations during bone development.
Other mutant lines have been analysed in collaboration with labs that are specialized for certain organ systems or pathways. In collaboration with our partners from the European deafness consortium, we established model systems for deafness, progressive hearing loss and vestibular defects (Pau et al. 2005, Pau et al. 2004, Rhodes et al. 2004, Ahituv et al. 2004, Vreudge et al. 2003, Kiernan et al. 2001, Kiernan et al. 1999). We provided a mutant line with a missense point mutation in the cytoplasmic dynein heavy chain as model for ALS (amyotrophic lateral sclerosis). We showed progressive
A novel class of pigmentation mutants were identifi ed by dark skin (Dsk). Ten mutant lines provided insights into pigment accumulation (Fitch et al. 2003). In three mutant lines, which showed mutations in the Gnaq and Gna11 gene, we examined in a more detailed study the effects of G-protein mutations on skin colour (Van Ramsdonk et al. 2004).
We analysed two mutant lines with hair growth abnormalities (Rco2 and Rco3). A mutation in the Gsdm3 gene is causative for the alopecia phenotype in Rco2 mice (Runkel et al. 2004). The progressive alopecia in the Rco3 mutant was assigned to a 10-bp deletion in exon 1 of mK6irs1 (Peters et al. 2003).
We analysed eye mutants, which model cataracts, microphthalmia and glaucomas together with our collaborators from the Institute of Developmental Genetics (GSF), Institute of Human Genetics (GSF) and the Jackson laboratory (Hansdottir et al. 2004, Dalke et al. 2004, Graw et al. 2002a, Graw et al. 2002b, Graw et al. 2001a, Graw et al. 2001b, Graw et al. 2001c, Graw et al. 1999). A model system for amelogenesis imperfecta was analysed together with the Eppendorf Dental Hospital , (Seedorf et al. 2004), and a model for dwarfism, hyperghrelinemia, and obesity mutant was established together with the University of Marburg (Meyer et al. 2004).
In a QTL analysis, which we performed together with the Institute for Inhalation Biology (GSF) and the Gene mapping Center in Berlin, we found new QTL regions for lung function (Reinhard et al. 2002, Reinhard et al. 2005).
Future Objectives
We will continue the screening for new mutants in the ENU mutagenesis screen. We expect to establish 50 new mutant lines per year. The mutants will be mapped, uploaded to the Jax database and cryopreserved in the European Mouse Mutant Archive (EMMA). A detailed phenotype characterisation of mutants with bone or cartilage defects can be performed in our lab.
We will further contribute with our bone, cartilage and dysmorphology module to the German Mouse Clinic. The spectrum of secondary tests will be enlarged and improved.