Prolyl hydroxylation is a critical posttranslational modification that affects structure, function, and turnover of target proteins. Prolyl 3-hydroxylation occurs at only one position in the triple-helical domain of fibrillar collagen chains, and its biological significance is unknown. CRTAP shares homology with a family of putative prolyl 3-hydroxylases (P3Hs), but it does not contain their common dioxygenase domain. Loss of Crtap in mice causes an osteochondrodysplasia characterized by severe osteoporosis and decreased osteoid production. CRTAP can form a complex with P3H1 and cyclophilin B (CYPB), and Crtap-/- bone and cartilage collagens show decreased prolyl 3-hydroxylation. Moreover, mutant collagen shows evidence of overmodification, and collagen fibrils in mutant skin have increased diameter consistent with altered fibrillogenesis. In humans, CRTAP mutations are associated with the clinical spectrum of recessive osteogenesis imperfecta, including the type II and VII forms. Hence, dysregulation of prolyl 3-hydroxylation is a mechanism for connective tissue disease.

The fibrillar collagens provide structural scaffolding and strength to the extracellular matrices of connective tissues. We identified a partial sequence of a new fibrillar collagen gene in the NCBI databases and completed the sequence with bioinformatic approaches and 5' RACE. This gene, designated COL27A1, is approximately 156 kbp long and has 61 exons located on chromosome 9q32-33. The homologous mouse gene is located on chromosome 4. The gene encodes amino- and carboxyl-terminal propeptides similar to those in the 'minor' fibrillar collagens. The triple-helical domain is, however, shorter and contains 994 amino acids with two imperfections of the Gly-Xaa-Yaa repeat pattern. There were three sites of alternative RNA splicing, only one of which led to the intact mRNA that encodes this full-length collagen proalpha chain. Phylogenetic analyses indicated that COL27A1 forms a clade with COL24A1 that is distinct from the two known lineages of fibrillar collagens. Expression analyses of the mouse col27a1 gene demonstrated high expression in cartilage, the eye and ear, but also in lung and colon. It is likely that the major protein product of COL27A1, proalpha1(XXVII), is a component of the extracellular matrices of cartilage and these other tissues. Study of this collagen should yield insights into normal chondrogenesis, and provide clues to the pathogenesis of some chondrodysplasias and disorders of other tissues in which this gene is expressed.

Fibrillar collagens are well known for their links to human diseases, with which all have been associated except for the two most recently identified fibrillar collagens, type XXIV collagen and type XXVII collagen. To assess functions and potential disease phenotypes of type XXVII collagen, we examined its roles in zebrafish embryonic and post-embryonic development.