Deficiency of Cartilage-Associated Protein in Recessive Lethal Osteogenesis Imperfecta

Abstract

Classic osteogenesis imperfecta, an autosomal dominant disorder associated with osteoporosis and bone fragility, is caused by mutations in the genes for type I collagen. A recessive form of the disorder has long been suspected. Since the loss of cartilage-associated protein (CRTAP), which is required for post-translational prolyl 3-hydroxylation of collagen, causes severe osteoporosis in mice, we investigated whether CRTAP deficiency is associated with recessive osteogenesis imperfecta. Three of 10 children with lethal or severe osteogenesis imperfecta, who did not have a primary collagen defect yet had excess post-translational modification of collagen, were found to have a recessive condition resulting in CRTAP deficiency, suggesting that prolyl 3-hydroxylation of type I collagen is important for bone formation.

Genetic epidemiology, prevalence, and genotype–phenotype correlations in the Swedish population with osteogenesis imperfecta

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] On the contrary, here 15/32 families with no mutation in collagen I had a typical type I phenotype, and 25 additional families were excluded on the basis of a negative sequencing result in combination with an unclear clinical phenotype. These individuals may have a COL1A1 null allele caused by a non-exonic mutation missed here; however, another OI-related gene might be causative in some instances.…”

“…Dominant mutations in collagen type I are generally stated to be responsible for 90% of cases, while a plethora of other genes have been associated with non-collagen OI in recent years. [1][2][3][4][5][6][7][8][9][10][11][12][13] Collagen type I, encoded by COL1A1 and COL1A2, constitutes 85% of the organic matrix in skeletal tissue, and forms a framework for mineral deposition, rendering bone the tensile properties needed to withstand torsion and bending powers. Procollagen is a heterotrimer, with a helical 1014-amino acid-long central stretch of two α1-and one α2-chains, which is flanked by globular N-and C-terminal regions.…”

Osteogenesis imperfecta

“…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 …”

“…Homozygous or biallelic CRTAP null mutations 56 were identified in patients displaying a phenotype that overlapped with, but was distinct from, osteogenesis imperfecta type II and type III…”

“…Occasional survivors have severe growth deficiency and popcorn calcifications of epiphyses. 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 .…”