Targeted next-generation sequencing of genes associated with OI in humans (COL1A1, COL1A2, LEPRE1, SERPINH1, and CRTAP) revealed a G>A heterozygous mutation in the splice donor site of exon 18 of the COL1A2 gene (c.936 + 1G>A).
Several gene encoding proteins related to collagen metabolism have been described in some cases of autosomal recessive OI (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10).
Dominant inheritance of osteogenesis imperfecta (OI) is caused by mutations in COL1A1 or COL1A2, the genes that encode type I collagen, and CRTAP, LEPRE1, PPIB, FKBP10, SERPINH1, and SP7 mutations were recently detected in a minority of patients with autosomal recessive OI.
The majority of remaining affected individuals have recessively inherited forms of OI with the causative variants in the more recently discovered genes CRTAP, FKBP10, LEPRE1,PLOD2, PPIB, SERPINF1, SERPINH1 and SP7, or in other yet undiscovered genes.
Three proteins, cartilage-associated protein (CRTAP), prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene), and the prolyl cis-trans isomerase cyclophilin-B (PPIB), form a complex that is required for fibrillar collagen 3-prolyl-hydroxylation, and mutations in each gene have been shown to cause recessive forms of OI.
These findings suggest that prolyl cis-trans isomerase may be required to effectively fold the proline-rich regions of the C-terminal propeptide to allow proα chain association and suggest an order of action for CRTAP, P3H1 and CYPB in procollagen biosynthesis and pathogenesis of OI.
Mutations in type I collagen result in autosomal dominant osteogenesis imperfecta, whereas mutations in either of two components of the collagen prolyl 3-hydroxylation complex (cartilage-associated protein [CRTAP] and prolyl 3-hydroxylase 1 [P3H1]) cause autosomal recessive osteogenesis imperfecta with rhizomelia (shortening of proximal segments of upper and lower limbs) and delayed collagen folding.
Mutations in CRTAP (coding for cartilage-associated protein), LEPRE1 (coding for prolyl 3-hydroxylase 1 [P3H1]) or PPIB (coding for Cyclophilin B [CYPB]) cause recessive forms of osteogenesis imperfecta and loss or decrease of type I collagen prolyl 3-hydroxylation.
Two of the genes encoding proteins involved in that enzyme complex, LEPRE1 and cartilage-associated protein, when mutated have been shown to cause autosomal recessive osteogenesis imperfecta, which has a moderate to severe clinical phenotype, often indistinguishable from osteogenesis imperfecta types II or III.
The discovery of mutations involving CRTAP and LEPRE1 genes in severe/lethal and recessively inherited osteogenesis imperfecta has provided partial answers to questions about 'other' osteogenesis imperfecta genes in patients with an osteogenesis imperfecta phenotype but no COL1A1 and COL1A2 mutations.
This result and the fact that CyPB is demonstrable independent of CRTAP and P3H1, along with reported decreased 3-prolyl hydroxylation due to deficiency of CRTAP lacking the catalytic hydroxylation domain and the known function of CyPB as a cis-trans isomerase, suggest that recessive OI is caused by a dysfunctional P3H1/CRTAP/CyPB complex rather than by the lack of 3-prolyl hydroxylation of a single proline residue in the alpha1 chains of collagen type I.
Although it seems that one important feature of autosomal recessive OI due to CRTAP mutations is the higher consistency of radiological features with OI type II-B/III, differentiation between autosomal dominant and autosomal recessive OI on the basis of clinical, radiological and biochemical investigations proves difficult in the affected individuals reported here.
Recessive forms of osteogenesis imperfecta (OI) may be caused by mutations in LEPRE1, encoding prolyl 3-hydroxylase-1 (P3H1) or in CRTAP, encoding cartilage associated protein.
Investigation of recessive forms of OI particularly reported among South African blacks have revealed mutations involving both the CRTAP gene and the leucine proline-enriched proteoglycan 1 (LEPRE1) gene, each involved in collagen proline-3 hydroxylation.
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.