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Pseudoachondroplasia and Multiple Epiphyseal Dysplasia: Molecular Genetics, Disease Mechanisms and Therapeutic Targets.
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Professor Michael Briggs
Dr Peter Bell
Dr Katarzyna Pirog
Briggs MD, Bell PA, Piróg KA
Grässel S; Aszódi A
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© Springer International Publishing Switzerland 2017. Genetic skeletal diseases (GSDs) are a diverse and complex group of over 450 rare diseases that affect the development and homoeostasis of the skeleton. Although individually rare, as a group of related genetic skeletal diseases, they have an overall prevalence of at least 1 per 4000 children, which extrapolates to a minimum of 225,000 people in the European Union, and this extensive burden in pain and disability leads to poor quality of life and high healthcare costs. Dominant-negative (qualitative) defects in numerous cartilage structural proteins result in a broad range of GSDs, and this chapter will focus on a disease spectrum resulting from mutations in the glycoproteins, cartilage oligomeric matrix protein (COMP), type IX collagen and matrilin-3, which together cause a continuum of phenotypes that are amongst the most common of the autosomal dominant GSDs. Pseudoachondroplasia (PSACH) and autosomal dominant multiple epiphyseal dysplasia (MED) define a disease spectrum typified by varying degrees of shortlimbed dwarfism, joint pain with stiffness and early-onset osteoarthritis (OA). The generation and deep phenotyping of a range of genetic cell and mouse models of the PSACH and MED disease spectrum has allowed the disease mechanisms to be characterised in detail. Furthermore, the generation of novel phenocopies to model specific disease mechanisms has confirmed the importance of endoplasmic reticulum stress, reduced chondrocyte proliferation and increased dysregulated apoptosis as key indicators of growth plate dysplasia and eventually reduced bone growth. Lastly, new insight into disease-related musculoskeletal complications such as myopathy, ligamentous laxity and tendinopathy has been gained through the analysis of mouse models of the PSACH and MED disease spectrum.
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