10 Introduction Osteogenesis Imperfecta (OI) is a rare congenital connective tissue disease with a prevalence of 6.5 per 100,000 live births 1,2. OI is often referred to as “brittle bone disease” because fragile bones and high fracture prevalence are one of its most prominent features. However, the features of OI are much broader as the underlying problem in most cases involves an abnormality in collagen type 1 production. Collagen type 1 is abundant in bones, teeth, ligaments and tendons, and to a lesser extent in sclera, blood vessels and internal organs 3. Therefore, abnormalities and symptoms can occur in all the above-mentioned tissues and organs in OI and can affect the quality of life of people with OI in different ways 4. This thesis addresses quality of life in OI and the bleeding tendency, one of the abnormalities that is often mentioned but scarcely investigated in OI. This introductory chapter provides background information on OI and is followed by a description of the aims and outline of the thesis. Osteogenesis Imperfecta Etiology of OI The biosynthesis of collagen is a complex process in which even minor disruptions lead to a number of serious diseases. Each protein must be properly folded and modified to become functional. Basic steps in the successful production and maturation of proteins are synthesis, posttranslational modifications, folding, quality control, and transport. The collagen type 1 molecule has a triple helix structure consisting of two α1 chains and one α2 chain. Of all OI patients, approximately 85-90% have an autosomal dominant pathogenic variant in either the COL1A1 or the COL1A2 gene, which encodes for the collagen type 1 α1 chain and collagen type 1 α2 chain, respectively 5. The cells that convert these mutations to proteins produce a mixture of normal and abnormal collagen 6. Recently, recessive, dominant, and X-linked variants in several genes have been shown to cause defects in proteins responsible for transcription, synthesis, and post-translational modification. In addition, chaperone proteins, retrograde transport, extracellular processing of procollagen for bone synthesis, transport of type 1 collagen, matrix mineralization, and osteoblast differentiation are affected by pathogenic gene variants. All these genetic defects may cause OI 3,7. The resulting phenotype can range from very mild to lethal, depending in part on which of the alpha strands is affected and the position and nature of the pathogenic variant (Table 1). Classification In addition to heterogeneity at the molecular level, OI is also a clinically heterogeneous disorder and several researchers have attempted to develop a useful, understandable, and comprehensive classification for it. The most widely used classification is the one developed by Sillence et al. 9 in 1979,
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