2.5. Mutations in human collagen genes

The critical roles of collagens in the vertebrate body are illustrated by the wide spectrum of diseases caused by aberrations of collagen biosynthesis or mutations in collagen genes. Briefly, the correct amount of collagen in a given tissue is important. Excessive collagen accumulation leads to fibrosis and impairment of normal functioning of the affected organ, whereas decreased collagen synthesis leads to delayed wound or fracture healing. More than 1000 mutations have been characterized in 23 collagen genes for 13 out of more than 20 collagen types, as well as in two genes encoding collagen processing enzymes. These mutations result in heritable disorders with a broad range of clinical phenotypes (Table 3. and for reviews, see Kivirikko, 1993; Prockop & Kivirikko, 1995; Kuivaniemi et al., 1997; Myllyharju & Kivirikko, 2001).

Diseases caused by collagen gene mutations include bone disorders such as osteogenesis imperfecta (OI) and some forms of osteoporosis, as well as cartilage disorders such as many chondrodysplasias and some forms of osteoarthritis and intervertebral disc disease. Several subtypes of Ehlers-Danlos syndrome (EDS), a heterogeneous group of heritable disorders characterized by joint and skin changes and the rupture of arteries or other hollow organs, are linked to mutations in the collagen genes, as are the renal disease Alport syndrome, muscle disease Bethlem myopathy, certain subtypes of a skin disease epidermolysis bullosa (EB), a rare genetic disease characterized by eye and cranial defects called Knobloch syndrome, and some forms of arterial aneurysms. The most recent addition to the list of diseases caused by collagen mutations is corneal endothelial dystrophy, which is caused by mutations in the COL8A2 gene (Biswas et al., 2001).

Most of the mutations underlying these diseases are single base substitutions converting a codon for the obligatory glycine in the Gly-X-Y –triplet to a bulkier amino acid. However, other amino acid substitutions as well as deletions, insertions, duplications and complex rearrangements, have also been identified (for reviews, see Kivirikko, 1993; Prockop & Kivirikko, 1995; Kuivaniemi et al., 1997; Myllyharju & Kivirikko, 2001). The consequences of the mutations vary depending on their nature and location in the collagen chain, and thus mutations in the same gene can cause disease phenotypes ranging from lethal and severe forms of a disease to relatively mild forms, or just confer a predisposition for a certain disease. Generally, mutations that cause the synthesis of abnormal collagen chains, which can still associate with other chains, cause more severe phenotypes than null alleles or mutations that prevent chain association, due to the dominant-negative effect, or “procollagen suicide”. Accordingly, the effect of the mutation is amplified because the incorporation of mutant chains into collagen molecule prevents proper folding of the collagen triple helix, leading to the degradation of both the normal and mutant chains. Alternatively, the abnormal α-chains may allow the formation of collagen triple helix, but exert conformational changes in the overall structure of the collagen molecule, which may interfere with the normal supramolecular assembly of the collagen molecules and lead to impaired function of such assemblies (Prockop, 1990).