CRTAP Is Required for Prolyl 3- Hydroxylation and Mutations Cause Recessive Osteogenesis Imperfecta

Abstract

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.

Osteogenesis imperfecta

“…By con trast, among West Africans in Ghana and Nigeria, the carrier frequency for this allele is 1.5% and would result in an incidence of lethal recessive osteogenesis imper fecta equal to the incidence of de novo mutations in type I collagen 11 . Among First Nations people in north ern Ontario, Canada, a single deep intronic vari ant results in the use of a cryptic exon that destabilizes the CRTAP (which encodes cartilage associated protein) mRNA, and is responsible for the recessive osteogenesis imperfecta type VII 10,13 . As is the case for many recessive disorders, some populations harbour a single allele that accounts for the majority of individuals with a particular phenotype: a single exon deletion in TMEM38B found in individuals from Saudi Arabia 14 ; a single frameshift in FKBP10 found in individuals from Turkey 15 ; and a mis sense mutation in WNT1 in the Hmong people from Vietnam and China 16 .…”

“…During this phase, 65 kDa FK506 binding protein (FKBP65; encoded by FKBP10) and a complex formed by P3H1 -CRTAPPPIase B (peptidyl prolyl cis-trans isomerase B) -seem to play a crucial part. The complex is involved in the hydroxyl ation of proline 986 of the collagen α1(I) chain and α1(II) chain and proline 707 of the α2(I) chain 13,[19][20][21] , which are thought to be important for supramolecular assembly of collagen fibrils and to serve as binding sites for chaperones or small leucine rich proteoglycans 22 . Beyond its prolyl 3 hydroxylase activity, the com plex functions as a PPIase and chaperone for collagen folding 13,19,23 .…”

“…The complex is involved in the hydroxyl ation of proline 986 of the collagen α1(I) chain and α1(II) chain and proline 707 of the α2(I) chain 13,[19][20][21] , which are thought to be important for supramolecular assembly of collagen fibrils and to serve as binding sites for chaperones or small leucine rich proteoglycans 22 . Beyond its prolyl 3 hydroxylase activity, the com plex functions as a PPIase and chaperone for collagen folding 13,19,23 . Indeed, the fast propagation of the triple helix requires the isomerization of cis peptide bonds that convert proline residues into trans configuration, mainly by PPIase B 24 (FIG.…”

“…The crucial role of post translational modification and proper folding of type I procollagen in the patho genesis of osteogenesis imperfecta emerged from the identifi cation of patients with recessive mutations in genes encoding proteins that have an important role in these processes, for example, CRTAP 13,56 …”

“…CRTAP deficiency causes severely reduced hydroxylation of proline 986 of the α1(I) chain and delayed helix folding and consequent over modification of the type I collagen helical region by LH1 and P4H1 (REFS 13,56). Crtap knockout mice exhibit a severe osteochondrodysplasia 13 .…”