Collagen is the most abundant protein family in the mammalian body. More than 30 dispersed genes encode the protein products that form more than 19 different types of collagens that are distributed in a characteristic fashion among tissues.

Collagens are proteins that contain three chains wound in a triple helix. The biosynthesis is complex. Individual precursor chains are synthesized on membrane-bound polyribosomes. During transfer of the growing chain into the lumen of the rough endoplasmic reticulum, certain prolyl and lysyl residues in the triple-helical domain are hydroxylated and some hydroxylysyl residues are glycosylated. Assembly of the three chains in the rough endoplasmic reticulum is mediated by structures in the C-terminal propeptide domains of each chain and folding of the triple helix occurs from the C-terminal end of the molecule. Transport through the Golgi apparatus is accompanied by modification of oligosaccharide groups. Following secretion limited proteolysis leads to removal of the amino- and C-terminal propeptide extensions. Collagen molecules are stabilized in fibrillar structures or other meshworks through lysine-derived covalent intermolecular cross-links.

Disorders presently known to result from alterations in the structure and function of collagens affect the genes of collagens type I, II, III, IV, V, VI, VII, IX, X, XI, and XVII, and the enzymes lysyl hydroxylase and type I procollagen N-proteinase involved in the posttranslational modification of collagens.

The clinical heterogeneity apparent in the osteogenesis imperfecta (OI) phenotypes is a reflection of the underlying molecular heterogeneity. Mutations that affect the synthesis of the proα1(I) chains of type I collagen generally result in the relatively mild OI type I phenotype. Multiexon deletions or insertions in the COL1A1 and COL1A2 genes that encode the chains of type I collagen generally result in the lethal OI type II phenotype. The phenotypic effects of point mutations that result in substitutions for glycine residues in the triple-helical domains of proα1(I) of proα2(I) chains depend on the chain in which the mutation occurs, the location of the substitution within the chain, and the nature of the substituting amino acid.

The molecular basis of the Ehlers-Danlos syndrome (EDS) is heterogeneous. EDS type I and II result from mutations in the type V collagen genes and, possibly, in tenascin X. EDS type IV results from mutations that affect the synthesis, structure, or secretion of type III collagen. EDS type VI is a recessively inherited disorder that results from lack of lysyl hydroxylation. EDS type VII usually results from loss of the substrate sequence for the N-terminal procollagen protease in one of the chains of type I procollagen or from mutations in the enzyme itself.

Chondrodysplasias, including spondyloepiphyseal dysplasia, achondrogenesis, and some forms of Stickler syndrome result from mutations in type II collagen genes. Other forms of chondrodysplasia, Stickler syndrome type II and II, otospondyomegaepiphyseal dysplasia, and Marshall syndrome results from mutations in the closely related type XI collagen genes, while mutations in type IX collagen produce a form of multiple epiphyseal dysplasia. The nature of the phenotypic effect of these mutations depends on the character and location of the mutation in the fibrillar collagen genes in a manner similar to that seen in OI.

The X-linked form of Alport syndrome arises from mutations in the COL4A5 gene with an unusual form that involves renal disease and esophageal leiomyomatosis arising from deletions involving the contiguous COL4A5 and COL4A6 genes. Recessive forms result from mutations in the contiguous COL4A3 and COL4A4 genes.

Bethlem myopathy results from mutations in any of the three chains of type VI collagen.

Mutations in type VII collagen result in the dystrophic forms of epidermolysis bullosa and other forms result from mutations in type XVII collagen genes.

The clinical consequences of mutations in collagen genes reflect the effects of the mutations on biosynthesis, assembly, posttranslational modification, secretion, fibrillogenesis, and interaction with other components of a complex extracellular matrix in which there is considerable molecular interaction.