Mutations in collagen genes: causes of rare and some common diseases in humans

Abstract

More than 70 mutations in the two structural genes for type I procollagen (COL1A1 and COL1A2) have been found in probands with osteogenesis imperfecta, a heritable disease of children characterized by fragility of bone and other tissues rich in type I collagen. The mutations include deletions, insertions, RNA splicing mutations, and single-base substitutions that convert a codon for glycine to a codon for an amino acid with a bulkier side chain. With a few exceptions, the most severe phenotypes of the disease are explained largely by synthesis of structurally defective pro alpha chains of type I procollagen that either interfere with the folding of the triple helix or with self-assembly of collagen into fibrils. The results emphasize the extent to which the zipperlike folding of the collagen triple helix and the self-assembly of collagen fibrils depend on the principle of nucleated growth whereby a few subunits form a nucleus and the nucleus is then propagated to generate a large structure with a precisely defined architecture. The principle of nucleated growth is a highly efficient mechanism for the assembly of large structures, but biological systems that depend extensively on nucleated growth are highly vulnerable to mutations that cause synthesis of structurally abnormal but partially functional subunits. Recently, several mutations in three other collagen genes (COL2A1, COL3A1, and COL4A5) have been found in probands with genetic diseases involving tissues rich in these collagens. Most of the probands have rare genetic diseases but a few appear to have phenotypes that are difficult to distinguish from more common disorders such as osteoarthritis, osteoporosis, and aortic aneurysms. Therefore, the results suggest that mutations in procollagen genes may cause a wide spectrum of both rare and common human diseases.

Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans

“…The most common mutations that cause the more clinically significant forms of osteogenesis imperfecta result in substitutions for one of the invariant glycine residues in the triple helical domain of the two chains of type I collagen [Kuivaniemi et al, 1991;Prockop and Kivirikko, 1984]. In the coding sequence of the triple helical domain, which can be written GGNNNNNNN 338 , substitutions at either G will cause a substitution for glycine.…”

Predicting the Clinical Lethality of Osteogenesis Imperfecta from Collagen Glycine Mutations

“…However, a statistically significant correlation between the stability of the mutated triplet and lethality was not found when this model was applied to an updated set of mutations (9). Others have examined the role of the global stability of the protein on phenotype, but a clear association has not yet been identified (16)(17)(18)(19).…”

Gene therapy approaches for osteogenesis imperfecta

“…Gene therapy for OI treatment is complicated by the genetic heterogeneity of the disease and the fact that over 100 different mutations have been identified in the genes that code for the proa1 and proa2 chains. 3,4 Most OI mutations are dominant negative, the most common being point mutations that substitute the conserved glycine in the helical region of either proa1 or proa2 chains of type I collagen with charged amino acids or amino acids having bulky side chains. 3,14,16 Proa chains with such mutations are incorporated in the triple helical assembly with the normal chains and in so doing they destabilize the triple helical conformation of the collagen molecules.…”

“…Over 100 different mutations have been identified in the genes that encode the proa1(I) and the proa2(I) polypeptide chains that comprise the type I collagen molecules. 3,4 The majority of these mutations are dominant negative; thus, gene therapy approaches for OI will require silencing of the expression of the genes that encode abnormal collagen alleles before replacement of the mutated gene. The repetitive nature of the collagen amino-acid sequence, however, creates difficulties in the design of the antisense gene therapy approaches that only target the expression of the abnormal collagen alleles.…”