The Experts below are selected from a list of 78 Experts worldwide ranked by ideXlab platform
Hans Peter Bachinger - One of the best experts on this subject based on the ideXlab platform.
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an additional function of the rough endoplasmic reticulum Protein complex prolyl 3 hydroxylase 1 Cartilage Associated Protein cyclophilin b the cxxxc motif reveals disulfide isomerase activity in vitro
Journal of Biological Chemistry, 2013Co-Authors: Yoshihiro Ishikawa, Hans Peter BachingerAbstract:Abstract Collagen biosynthesis occurs in the rough endoplasmic reticulum, and many molecular chaperones and folding enzymes are involved in this process. The folding mechanism of type I procollagen has been well characterized, and Protein disulfide isomerase (PDI) has been suggested as a key player in the formation of the correct disulfide bonds in the noncollagenous carboxyl-terminal and amino-terminal propeptides. Prolyl 3-hydroxylase 1 (P3H1) forms a hetero-trimeric complex with Cartilage-Associated Protein and cyclophilin B (CypB). This complex is a multifunctional complex acting as a prolyl 3-hydroxylase, a peptidyl prolyl cis-trans isomerase, and a molecular chaperone. Two major domains are predicted from the primary sequence of P3H1: an amino-terminal domain and a carboxyl-terminal domain corresponding to the 2-oxoglutarate- and iron-dependent dioxygenase domains similar to the α-subunit of prolyl 4-hydroxylase and lysyl hydroxylases. The amino-terminal domain contains four CXXXC sequence repeats. The primary sequence of Cartilage-Associated Protein is homologous to the amino-terminal domain of P3H1 and also contains four CXXXC sequence repeats. However, the function of the CXXXC sequence repeats is not known. Several publications have reported that short peptides containing a CXC or a CXXC sequence show oxido-reductase activity similar to PDI in vitro. We hypothesize that CXXXC motifs have oxido-reductase activity similar to the CXXC motif in PDI. We have tested the enzyme activities on model substrates in vitro using a GCRALCG peptide and the P3H1 complex. Our results suggest that this complex could function as a disulfide isomerase in the rough endoplasmic reticulum.
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an additional function of the rough endoplasmic reticulum Protein complex prolyl 3 hydroxylase 1 Cartilage Associated Protein cyclophilin b the cxxxc motif reveals disulfide isomerase activity in vitro
Journal of Biological Chemistry, 2013Co-Authors: Yoshihiro Ishikawa, Hans Peter BachingerAbstract:Collagen biosynthesis occurs in the rough endoplasmic reticulum, and many molecular chaperones and folding enzymes are involved in this process. The folding mechanism of type I procollagen has been well characterized, and Protein disulfide isomerase (PDI) has been suggested as a key player in the formation of the correct disulfide bonds in the noncollagenous carboxyl-terminal and amino-terminal propeptides. Prolyl 3-hydroxylase 1 (P3H1) forms a hetero-trimeric complex with Cartilage-Associated Protein and cyclophilin B (CypB). This complex is a multifunctional complex acting as a prolyl 3-hydroxylase, a peptidyl prolyl cis-trans isomerase, and a molecular chaperone. Two major domains are predicted from the primary sequence of P3H1: an amino-terminal domain and a carboxyl-terminal domain corresponding to the 2-oxoglutarate- and iron-dependent dioxygenase domains similar to the α-subunit of prolyl 4-hydroxylase and lysyl hydroxylases. The amino-terminal domain contains four CXXXC sequence repeats. The primary sequence of Cartilage-Associated Protein is homologous to the amino-terminal domain of P3H1 and also contains four CXXXC sequence repeats. However, the function of the CXXXC sequence repeats is not known. Several publications have reported that short peptides containing a CXC or a CXXC sequence show oxido-reductase activity similar to PDI in vitro. We hypothesize that CXXXC motifs have oxido-reductase activity similar to the CXXC motif in PDI. We have tested the enzyme activities on model substrates in vitro using a GCRALCG peptide and the P3H1 complex. Our results suggest that this complex could function as a disulfide isomerase in the rough endoplasmic reticulum. Background: The function of the CXXXC motifs in P3H1 and CRTAP has not been previously characterized. Results: The model GCRALCG peptide and the P3H1·CRTAP·CypB complex show disulfide isomerase activity in vitro. Conclusion: Our results suggest that this complex could function as a disulfide isomerase. Significance: This indicates an additional function of the P3H1 complex in the rER.
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Biochemical characterization of the prolyl 3-hydroxylase 1.Cartilage-Associated Protein.cyclophilin B complex.
The Journal of biological chemistry, 2009Co-Authors: Yoshihiro Ishikawa, Jackie Wirz, Janice A. Vranka, Kazuhiro Nagata, Hans Peter BachingerAbstract:The rough endoplasmic reticulum-resident Protein complex consisting of prolyl 3-hydroxylase 1 (P3H1), Cartilage-Associated Protein (CRTAP), and cyclophilin B (CypB) can be isolated from chick embryos on a gelatin-Sepharose column, indicating some involvement in the biosynthesis of procollagens. Prolyl 3-hydroxylase 1 modifies a single proline residue in the α chains of type I, II, and III collagens to (3S)-hydroxyproline. The peptidyl-prolyl cis-trans isomerase activity of cyclophilin B was shown previously to catalyze the rate of triple helix formation. Here we show that cyclophilin B in the complex shows peptidyl-prolyl cis-trans isomerase activity and that the P3H1·CRTAP·CypB complex has another important function: it acts as a chaperone molecule when tested with two classical chaperone assays. The P3H1·CRTAP·CypB complex inhibited the thermal aggregation of citrate synthase and was active in the denatured rhodanese refolding and aggregation assay. The chaperone activity of the complex was higher than that of Protein-disulfide isomerase, a well characterized chaperone. The P3H1·CRTAP·CypB complex also delayed the in vitro fibril formation of type I collagen, indicating that this complex is also able to interact with triple helical collagen and acts as a collagen chaperone.
Yoshihiro Ishikawa - One of the best experts on this subject based on the ideXlab platform.
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an additional function of the rough endoplasmic reticulum Protein complex prolyl 3 hydroxylase 1 Cartilage Associated Protein cyclophilin b the cxxxc motif reveals disulfide isomerase activity in vitro
Journal of Biological Chemistry, 2013Co-Authors: Yoshihiro Ishikawa, Hans Peter BachingerAbstract:Abstract Collagen biosynthesis occurs in the rough endoplasmic reticulum, and many molecular chaperones and folding enzymes are involved in this process. The folding mechanism of type I procollagen has been well characterized, and Protein disulfide isomerase (PDI) has been suggested as a key player in the formation of the correct disulfide bonds in the noncollagenous carboxyl-terminal and amino-terminal propeptides. Prolyl 3-hydroxylase 1 (P3H1) forms a hetero-trimeric complex with Cartilage-Associated Protein and cyclophilin B (CypB). This complex is a multifunctional complex acting as a prolyl 3-hydroxylase, a peptidyl prolyl cis-trans isomerase, and a molecular chaperone. Two major domains are predicted from the primary sequence of P3H1: an amino-terminal domain and a carboxyl-terminal domain corresponding to the 2-oxoglutarate- and iron-dependent dioxygenase domains similar to the α-subunit of prolyl 4-hydroxylase and lysyl hydroxylases. The amino-terminal domain contains four CXXXC sequence repeats. The primary sequence of Cartilage-Associated Protein is homologous to the amino-terminal domain of P3H1 and also contains four CXXXC sequence repeats. However, the function of the CXXXC sequence repeats is not known. Several publications have reported that short peptides containing a CXC or a CXXC sequence show oxido-reductase activity similar to PDI in vitro. We hypothesize that CXXXC motifs have oxido-reductase activity similar to the CXXC motif in PDI. We have tested the enzyme activities on model substrates in vitro using a GCRALCG peptide and the P3H1 complex. Our results suggest that this complex could function as a disulfide isomerase in the rough endoplasmic reticulum.
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an additional function of the rough endoplasmic reticulum Protein complex prolyl 3 hydroxylase 1 Cartilage Associated Protein cyclophilin b the cxxxc motif reveals disulfide isomerase activity in vitro
Journal of Biological Chemistry, 2013Co-Authors: Yoshihiro Ishikawa, Hans Peter BachingerAbstract:Collagen biosynthesis occurs in the rough endoplasmic reticulum, and many molecular chaperones and folding enzymes are involved in this process. The folding mechanism of type I procollagen has been well characterized, and Protein disulfide isomerase (PDI) has been suggested as a key player in the formation of the correct disulfide bonds in the noncollagenous carboxyl-terminal and amino-terminal propeptides. Prolyl 3-hydroxylase 1 (P3H1) forms a hetero-trimeric complex with Cartilage-Associated Protein and cyclophilin B (CypB). This complex is a multifunctional complex acting as a prolyl 3-hydroxylase, a peptidyl prolyl cis-trans isomerase, and a molecular chaperone. Two major domains are predicted from the primary sequence of P3H1: an amino-terminal domain and a carboxyl-terminal domain corresponding to the 2-oxoglutarate- and iron-dependent dioxygenase domains similar to the α-subunit of prolyl 4-hydroxylase and lysyl hydroxylases. The amino-terminal domain contains four CXXXC sequence repeats. The primary sequence of Cartilage-Associated Protein is homologous to the amino-terminal domain of P3H1 and also contains four CXXXC sequence repeats. However, the function of the CXXXC sequence repeats is not known. Several publications have reported that short peptides containing a CXC or a CXXC sequence show oxido-reductase activity similar to PDI in vitro. We hypothesize that CXXXC motifs have oxido-reductase activity similar to the CXXC motif in PDI. We have tested the enzyme activities on model substrates in vitro using a GCRALCG peptide and the P3H1 complex. Our results suggest that this complex could function as a disulfide isomerase in the rough endoplasmic reticulum. Background: The function of the CXXXC motifs in P3H1 and CRTAP has not been previously characterized. Results: The model GCRALCG peptide and the P3H1·CRTAP·CypB complex show disulfide isomerase activity in vitro. Conclusion: Our results suggest that this complex could function as a disulfide isomerase. Significance: This indicates an additional function of the P3H1 complex in the rER.
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prolyl 3 hydroxylase 1 null mice display abnormalities in fibrillar collagen rich tissues such as tendons skin and bones
Journal of Biological Chemistry, 2010Co-Authors: Janice A. Vranka, Yoshihiro Ishikawa, Elena Pokidysheva, Lauren Hayashi, Keith Zientek, Kazunori Mizuno, Kerry Maddox, Sara F Tufa, Douglas R KeeneAbstract:Abstract Osteogenesis imperfecta (OI) is a skeletal disorder primarily caused by mutations in the type I collagen genes. However, recent investigations have revealed that mutations in the genes encoding for Cartilage-Associated Protein (CRTAP) or prolyl 3-hydroxylase 1 (P3H1) can cause a severe, recessive form of OI. These reports show minimal 3-hydroxylation of key proline residues in type I collagen as a result of CRTAP or P3H1 deficiency and demonstrate the importance of P3H1 and CRTAP to bone structure and development. P3H1 and CRTAP have previously been shown to form a stable complex with cyclophilin B, and P3H1 was shown to catalyze the 3-hydroxylation of specific proline residues in procollagen I in vitro. Here we describe a mouse model in which the P3H1 gene has been inactivated. Our data demonstrate abnormalities in collagen fibril ultrastructure in tendons from P3H1 null mice by electron microscopy. Differences are also seen in skin architecture, as well as in developing limbs by histology. Additionally bone mass and strength were significantly lower in the P3H1 mice as compared with wild-type littermates. Altogether these investigations demonstrate disturbances of collagen fiber architecture in tissues rich in fibrillar collagen, including bone, tendon, and skin. This model system presents a good opportunity to study the underlying mechanisms of recessive OI and to better understand its effects in humans.
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Biochemical characterization of the prolyl 3-hydroxylase 1.Cartilage-Associated Protein.cyclophilin B complex.
The Journal of biological chemistry, 2009Co-Authors: Yoshihiro Ishikawa, Jackie Wirz, Janice A. Vranka, Kazuhiro Nagata, Hans Peter BachingerAbstract:The rough endoplasmic reticulum-resident Protein complex consisting of prolyl 3-hydroxylase 1 (P3H1), Cartilage-Associated Protein (CRTAP), and cyclophilin B (CypB) can be isolated from chick embryos on a gelatin-Sepharose column, indicating some involvement in the biosynthesis of procollagens. Prolyl 3-hydroxylase 1 modifies a single proline residue in the α chains of type I, II, and III collagens to (3S)-hydroxyproline. The peptidyl-prolyl cis-trans isomerase activity of cyclophilin B was shown previously to catalyze the rate of triple helix formation. Here we show that cyclophilin B in the complex shows peptidyl-prolyl cis-trans isomerase activity and that the P3H1·CRTAP·CypB complex has another important function: it acts as a chaperone molecule when tested with two classical chaperone assays. The P3H1·CRTAP·CypB complex inhibited the thermal aggregation of citrate synthase and was active in the denatured rhodanese refolding and aggregation assay. The chaperone activity of the complex was higher than that of Protein-disulfide isomerase, a well characterized chaperone. The P3H1·CRTAP·CypB complex also delayed the in vitro fibril formation of type I collagen, indicating that this complex is also able to interact with triple helical collagen and acts as a collagen chaperone.
Aileen M Barnes - One of the best experts on this subject based on the ideXlab platform.
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substitution of murine type i collagen a1 3 hydroxylation site alters matrix structure but does not recapitulate osteogenesis imperfecta bone dysplasia
Matrix Biology, 2020Co-Authors: Wayne A Cabral, Nadja Fratzlzelman, Maryann Weis, Joseph E Perosky, Adrienne Alimasa, Rachel Harris, Heeseog Kang, Elena Makareeva, Aileen M Barnes, Paul RoschgerAbstract:Abstract Null mutations in CRTAP or P3H1, encoding Cartilage-Associated Protein and prolyl 3-hydroxylase 1, cause the severe bone dysplasias, types VII and VIII osteogenesis imperfecta. Lack of either Protein prevents formation of the ER prolyl 3-hydroxylation complex, which catalyzes 3Hyp modification of types I and II collagen and also acts as a collagen chaperone. To clarify the role of the A1 3Hyp substrate site in recessive bone dysplasia, we generated knock-in mice with an α1(I)P986A substitution that cannot be 3-hydroxylated. Mutant mice have normal survival, growth, femoral breaking strength and mean bone mineralization. However, the bone collagen HP/LP crosslink ratio is nearly doubled in mutant mice, while collagen fibril diameter and bone yield energy are decreased. Thus, 3-hydroxylation of the A1 site α1(I)P986 affects collagen crosslinking and structural organization, but its absence does not directly cause recessive bone dysplasia. Our study suggests that the functions of the modification complex as a collagen chaperone are thus distinct from its role as prolyl 3-hydroxylase.
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a novel mutation in lepre1 that eliminates only the kdel er retrieval sequence causes non lethal osteogenesis imperfecta
PLOS ONE, 2012Co-Authors: Masaki Takagi, Maryann Weis, Aileen M Barnes, David R Eyre, Tomohiro Ishii, Naoko Amano, Mamoru Tanaka, Ryuji Fukuzawa, Gen Nishimura, Joan C MariniAbstract:Prolyl 3-hydroxylase 1 (P3H1), encoded by the LEPRE1 gene, forms a molecular complex with Cartilage-Associated Protein (CRTAP) and cyclophilin B (encoded by PPIB) in the endoplasmic reticulum (ER). This complex is responsible for one step in collagen post-translational modification, the prolyl 3-hydroxylation of specific proline residues, specifically α1(I) Pro986. P3H1 provides the enzymatic activity of the complex and has a Lys-Asp-Glu-Leu (KDEL) ER-retrieval sequence at the carboxyl terminus. Loss of function mutations in LEPRE1 lead to the Pro986 residue remaining unmodified and lead to slow folding and excessive helical post-translational modification of type I collagen, which is seen in both dominant and recessive osteogenesis imperfecta (OI). Here, we present the case of siblings with non-lethal OI due to novel compound heterozygous mutations in LEPRE1 (c.484delG and c.2155dupC). The results of RNA analysis and real-time PCR suggest that mRNA with c.2155dupC escapes from nonsense-mediated RNA decay. Without the KDEL ER- retrieval sequence, the product of the c.2155dupC variant cannot be retained in the ER. This is the first report of a mutation in LEPRE1 that eliminates only the KDEL ER-retrieval sequence, whereas other functional domains remain intact. Our study shows, for the first time, that the KDEL ER- retrieval sequence is essential for P3H1 functionality and that a defect in KDEL is sufficient for disease onset.
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lack of cyclophilin b in osteogenesis imperfecta with normal collagen folding
The New England Journal of Medicine, 2010Co-Authors: Aileen M Barnes, Wayne A Cabral, Maryann Weis, Elena Makareeva, Erin Carter, Weizhong Chang, Sergey Leikin, Charles N Rotimi, David R Eyre, Cathleen L RaggioAbstract:Summary Osteogenesis imperfecta is a heritable disorder that causes bone fragility. 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. We identified two siblings who had recessive osteogenesis imperfecta without rhizomelia. They had a homozygous start-codon mutation in the peptidyl-prolyl isomerase B gene (PPIB), which results in a lack of cyclophilin B (CyPB), the third component of the complex. The proband’s collagen had normal collagen folding and normal prolyl 3-hydroxylation, suggesting that CyPB is not the exclusive peptidyl-prolyl cis–trans isomerase that catalyzes the rate-limiting step in collagen folding, as is currently thought.
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Null mutations in LEPRE1 and CRTAP cause severe recessive osteogenesis imperfecta
Cell and Tissue Research, 2010Co-Authors: Joan C Marini, Wayne A Cabral, Aileen M BarnesAbstract:Classical osteogenesis imperfecta (OI) is a dominant genetic disorder of connective tissue caused by mutations in either of the two genes encoding type I collagen, COL1A1 and COL1A2 . Recent investigations, however, have generated a new paradigm for OI incorporating many of the prototypical features that distinguish dominant and recessive conditions, within a type I collagen framework. We and others have shown that the long-sought cause of the recessive form of OI, first postulated in the Sillence classification, lies in defects in the genes encoding Cartilage-Associated Protein ( CRTAP ) or prolyl 3-hydroxylase 1 (P3H1/ LEPRE1 ). Together with cyclophilin B ( PPIB ), CRTAP and P3H1 comprise the collagen prolyl 3-hydroxylation complex, which catalyzes a specific posttranslational modification of types I, II, and V collagen, and may act as a general chaperone. Patients with mutations in CRTAP or LEPRE1 have a lethal to severe osteochondrodystrophy that overlaps with Sillence types II and III OI but has distinctive features. Infants with recessive OI have white sclerae, undertubulation of the long bones, gracile ribs without beading, and a small to normal head circumference. Those who survive to childhood or the teen years have severe growth deficiency and extreme bone fragility. Most causative mutations result in null alleles, with the absence or severe reduction of gene transcripts and Proteins. As expected, 3-hydroxylation of the Pro986 residue is absent or severly reduced, but bone severity and survival length do not correlate with the extent of residual hydroxylation. Surprisingly, the collagen produced by cells with an absence of Pro986 hydroxylation has helical overmodification by lysyl hydroxylase and prolyl 4-hydroxylase, indicating that the folding of the collagen helix has been substantially delayed.
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deficiency of Cartilage Associated Protein in recessive lethal osteogenesis imperfecta
The New England Journal of Medicine, 2006Co-Authors: Aileen M Barnes, Wayne A Cabral, Maryann Weis, Elena Makareeva, Weizhong Chang, Sergey Leikin, David R Eyre, Roy Morello, Natalia V Kuznetsova, Thomas E UvegesAbstract: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.
Roy Morello - One of the best experts on this subject based on the ideXlab platform.
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dental and craniofacial defects in the crtap mouse model of osteogenesis imperfecta type vii
Developmental Dynamics, 2020Co-Authors: Sydney A Lenhart, Roy Morello, Milena Dimori, Emily Y Chu, Michael B Chavez, H F Wimer, Martha J Somerman, Brian L Foster, Nan E HatchAbstract:Background Inactivating mutations in the gene for Cartilage-Associated Protein (CRTAP) cause osteogenesis imperfecta type VII in humans, with a phenotype that can include craniofacial defects. Dental and craniofacial manifestations have not been a focus of case reports to date. We analyzed the craniofacial and dental phenotype of Crtap-/- mice by skull measurements, micro-computed tomography (micro-CT), histology, and immunohistochemistry. Results Crtap-/- mice exhibited a brachycephalic skull shape with fusion of the nasofrontal suture and facial bones, resulting in mid-face retrusion and a class III dental malocclusion. Loss of CRTAP also resulted in decreased dentin volume and decreased cellular cementum volume, though acellular cementum thickness was increased. Periodontal dysfunction was revealed by decreased alveolar bone volume and mineral density, increased periodontal ligament (PDL) space, ectopic calcification within the PDL, bone-tooth ankylosis, altered immunostaining of extracellular matrix Proteins in bone and PDL, increased pSMAD5, and more numerous osteoclasts on alveolar bone surfaces. Conclusions Crtap-/- mice serve as a useful model of the dental and craniofacial abnormalities seen in individuals with osteogenesis imperfecta type VII.
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expression characterization and functional implication of the collagen modifying leprecan Proteins in mouse gonadal tissue and mature sperm
Genetics 2018 Vol. 5 Pages 24-40, 2018Co-Authors: Sarah M Zimmerman, Roberta Besio, Melissa E Heardlipsmeyer, Milena Dimori, Patrizio Castagnola, Frances L Swain, Dana Gaddy, Alan B Diekman, Roy MorelloAbstract:The Leprecan Protein family which includes the prolyl 3-hydroxylase enzymes (P3H1, P3H2, and P3H3), the closely related Cartilage-Associated Protein (CRTAP), and SC65 (Synaptonemal complex 65, aka P3H4, LEPREL4), is involved in the post-translational modification of fibrillar collagens. Mutations in CRTAP, P3H1 and P3H2 cause human genetic diseases. We recently showed that SC65 forms a stable complex in the endoplasmic reticulum with P3H3 and lysyl hydroxylase 1 and that loss of this complex leads to defective collagen lysyl hydroxylation and causes low bone mass and skin fragility. Interestingly, SC65 was initially described as a synaptonemal complex-Associated Protein, suggesting a potential additional role in germline cells. In the present study, we describe the expression of SC65, CRTAP and other Leprecan Proteins in postnatal mouse reproductive organs. We detect SC65 expression in peritubular cells of testis up to 4 weeks of age but not in cells within seminiferous tubules, while its expression is maintained in ovarian follicles until adulthood. Similar to bone and skin, SC65 and P3H3 are also tightly co-expressed in testis and ovary. Moreover, we show that CRTAP, a Protein normally involved in collagen prolyl 3-hydroxylation, is highly expressed in follicles and stroma of the ovary and in testes interstitial cells at 4 weeks of age, germline cells and mature sperm. Importantly, CrtapKO mice have a mild but significant increase in morphologically abnormal mature sperm (17% increase compared to WT). These data suggest a role for the Leprecans in the post-translational modification of collagens expressed in the stroma of the reproductive organs. While we could not confirm that SC65 is part of the synaptonemal complex, the expression of CRTAP in the seminiferous tubules and in mature sperm suggest a role in the testis germ cell lineage and sperm morphogenesis.
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Role of Cartilage-Associated Protein in Skeletal Development
Current Osteoporosis Reports, 2010Co-Authors: Roy Morello, Frank RauchAbstract:The past 3 years have been exciting for collagen biologists and human geneticists studying the disease known as osteogenesis imperfecta (OI or brittle bone disease). Functional studies on Cartilage-Associated Protein (Crtap) have identified it as an essential component of a heterotrimeric, endoplasmic reticulum resident complex responsible for collagen prolyl 3-hydroxylation and chaperone function. Importantly, human mutations in the CRTAP gene have been Associated with recessive forms of OI. Although the function and in vivo biological significance of the 3-hydroxyproline modification are still poorly understood, studies on Crtap have led to the identification of additional genes in which mutations also cause recessive forms of OI. These discoveries have now focused the interest of geneticists on the endoplasmic reticulum that will require the help of biochemists to unravel the molecular dynamics and complexities of collagen folding.
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crtap and lepre1 mutations in recessive osteogenesis imperfecta
Human Mutation, 2008Co-Authors: Dustin Baldridge, Maryann Weis, David R Eyre, Roy Morello, Ulrike Schwarze, Jennifer Lennington, Terry Bertin, James M Pace, Melanie Pepin, Jennifer WalshAbstract:Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Recently, dysregulation of hydroxylation of a single proline residue at position 986 of both the triple-helical domains of type I collagen α1(I) and type II collagen α1(II) chains has been implicated in the pathogenesis of recessive forms of OI. Two Proteins, CRTAP, or Cartilage-Associated Protein, and prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis-trans isomerase cyclophilin-B (CYPB) to the unfolded collagen. In our screen of 78 subjects diagnosed with OI type II or III, we identified three probands with mutations in CRTAP and sixteen with mutations in LEPRE1. The latter group includes a mutation in patients from the Irish Traveller population, a genetically isolated community with increased incidence of OI. The clinical features resulting from CRTAP or LEPRE1 loss of function mutations were difficult to distinguish at birth. Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density. Interestingly, “popcorn” epiphyses may reflect underlying cartilaginous and bone dysplasia in this form of OI. These results expand the range of CRTAP/LEPRE1 mutations that result in recessive OI and emphasize the importance of distinguishing recurrence of severe OI of recessive inheritance from those that result from parental germline mosaicism for COL1A1 or COL1A2 mutations.
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deficiency of Cartilage Associated Protein in recessive lethal osteogenesis imperfecta
The New England Journal of Medicine, 2006Co-Authors: Aileen M Barnes, Wayne A Cabral, Maryann Weis, Elena Makareeva, Weizhong Chang, Sergey Leikin, David R Eyre, Roy Morello, Natalia V Kuznetsova, Thomas E UvegesAbstract: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.
Maryann Weis - One of the best experts on this subject based on the ideXlab platform.
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substitution of murine type i collagen a1 3 hydroxylation site alters matrix structure but does not recapitulate osteogenesis imperfecta bone dysplasia
Matrix Biology, 2020Co-Authors: Wayne A Cabral, Nadja Fratzlzelman, Maryann Weis, Joseph E Perosky, Adrienne Alimasa, Rachel Harris, Heeseog Kang, Elena Makareeva, Aileen M Barnes, Paul RoschgerAbstract:Abstract Null mutations in CRTAP or P3H1, encoding Cartilage-Associated Protein and prolyl 3-hydroxylase 1, cause the severe bone dysplasias, types VII and VIII osteogenesis imperfecta. Lack of either Protein prevents formation of the ER prolyl 3-hydroxylation complex, which catalyzes 3Hyp modification of types I and II collagen and also acts as a collagen chaperone. To clarify the role of the A1 3Hyp substrate site in recessive bone dysplasia, we generated knock-in mice with an α1(I)P986A substitution that cannot be 3-hydroxylated. Mutant mice have normal survival, growth, femoral breaking strength and mean bone mineralization. However, the bone collagen HP/LP crosslink ratio is nearly doubled in mutant mice, while collagen fibril diameter and bone yield energy are decreased. Thus, 3-hydroxylation of the A1 site α1(I)P986 affects collagen crosslinking and structural organization, but its absence does not directly cause recessive bone dysplasia. Our study suggests that the functions of the modification complex as a collagen chaperone are thus distinct from its role as prolyl 3-hydroxylase.
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a novel mutation in lepre1 that eliminates only the kdel er retrieval sequence causes non lethal osteogenesis imperfecta
PLOS ONE, 2012Co-Authors: Masaki Takagi, Maryann Weis, Aileen M Barnes, David R Eyre, Tomohiro Ishii, Naoko Amano, Mamoru Tanaka, Ryuji Fukuzawa, Gen Nishimura, Joan C MariniAbstract:Prolyl 3-hydroxylase 1 (P3H1), encoded by the LEPRE1 gene, forms a molecular complex with Cartilage-Associated Protein (CRTAP) and cyclophilin B (encoded by PPIB) in the endoplasmic reticulum (ER). This complex is responsible for one step in collagen post-translational modification, the prolyl 3-hydroxylation of specific proline residues, specifically α1(I) Pro986. P3H1 provides the enzymatic activity of the complex and has a Lys-Asp-Glu-Leu (KDEL) ER-retrieval sequence at the carboxyl terminus. Loss of function mutations in LEPRE1 lead to the Pro986 residue remaining unmodified and lead to slow folding and excessive helical post-translational modification of type I collagen, which is seen in both dominant and recessive osteogenesis imperfecta (OI). Here, we present the case of siblings with non-lethal OI due to novel compound heterozygous mutations in LEPRE1 (c.484delG and c.2155dupC). The results of RNA analysis and real-time PCR suggest that mRNA with c.2155dupC escapes from nonsense-mediated RNA decay. Without the KDEL ER- retrieval sequence, the product of the c.2155dupC variant cannot be retained in the ER. This is the first report of a mutation in LEPRE1 that eliminates only the KDEL ER-retrieval sequence, whereas other functional domains remain intact. Our study shows, for the first time, that the KDEL ER- retrieval sequence is essential for P3H1 functionality and that a defect in KDEL is sufficient for disease onset.
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lack of cyclophilin b in osteogenesis imperfecta with normal collagen folding
The New England Journal of Medicine, 2010Co-Authors: Aileen M Barnes, Wayne A Cabral, Maryann Weis, Elena Makareeva, Erin Carter, Weizhong Chang, Sergey Leikin, Charles N Rotimi, David R Eyre, Cathleen L RaggioAbstract:Summary Osteogenesis imperfecta is a heritable disorder that causes bone fragility. 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. We identified two siblings who had recessive osteogenesis imperfecta without rhizomelia. They had a homozygous start-codon mutation in the peptidyl-prolyl isomerase B gene (PPIB), which results in a lack of cyclophilin B (CyPB), the third component of the complex. The proband’s collagen had normal collagen folding and normal prolyl 3-hydroxylation, suggesting that CyPB is not the exclusive peptidyl-prolyl cis–trans isomerase that catalyzes the rate-limiting step in collagen folding, as is currently thought.
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crtap and lepre1 mutations in recessive osteogenesis imperfecta
Human Mutation, 2008Co-Authors: Dustin Baldridge, Maryann Weis, David R Eyre, Roy Morello, Ulrike Schwarze, Jennifer Lennington, Terry Bertin, James M Pace, Melanie Pepin, Jennifer WalshAbstract:Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Recently, dysregulation of hydroxylation of a single proline residue at position 986 of both the triple-helical domains of type I collagen α1(I) and type II collagen α1(II) chains has been implicated in the pathogenesis of recessive forms of OI. Two Proteins, CRTAP, or Cartilage-Associated Protein, and prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis-trans isomerase cyclophilin-B (CYPB) to the unfolded collagen. In our screen of 78 subjects diagnosed with OI type II or III, we identified three probands with mutations in CRTAP and sixteen with mutations in LEPRE1. The latter group includes a mutation in patients from the Irish Traveller population, a genetically isolated community with increased incidence of OI. The clinical features resulting from CRTAP or LEPRE1 loss of function mutations were difficult to distinguish at birth. Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density. Interestingly, “popcorn” epiphyses may reflect underlying cartilaginous and bone dysplasia in this form of OI. These results expand the range of CRTAP/LEPRE1 mutations that result in recessive OI and emphasize the importance of distinguishing recurrence of severe OI of recessive inheritance from those that result from parental germline mosaicism for COL1A1 or COL1A2 mutations.
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deficiency of Cartilage Associated Protein in recessive lethal osteogenesis imperfecta
The New England Journal of Medicine, 2006Co-Authors: Aileen M Barnes, Wayne A Cabral, Maryann Weis, Elena Makareeva, Weizhong Chang, Sergey Leikin, David R Eyre, Roy Morello, Natalia V Kuznetsova, Thomas E UvegesAbstract: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.