The Experts below are selected from a list of 405 Experts worldwide ranked by ideXlab platform
Joan C Marini - One of the best experts on this subject based on the ideXlab platform.
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Bruck syndrome 2 variant lacking congenital contractures and involving a novel compound heterozygous PLOD2 mutation.
Bone, 2019Co-Authors: Steven Mumm, Aileen M Barnes, Gary S. Gottesman, Deborah Wenkert, Philippe M. Campeau, Angela Nenninger, Margaret Huskey, Vinieth N. Bijanki, Deborah J. Veis, Joan C MariniAbstract:Abstract Bruck syndrome (BRKS) is the rare disorder that features congenital joint contractures often with pterygia and subsequent fractures, early on called osteogenesis imperfecta (OI) type XI (OMIM # 610968 ). Its two forms, BRKS1 (OMIM # 259450 ) and BRKS2 (OMIM # 609220 ), reflect autosomal recessive (AR) inheritance of FKBP10 and PLOD2 loss-of-function mutations, respectively. A 10-year-old girl was referred with blue sclera, osteopenia, poorly-healing fragility fractures, Wormian skull bones, cleft soft palate, congenital fusion of cervical vertebrae, progressive scoliosis, bell-shaped thorax, restrictive and reactive pulmonary disease, protrusio acetabuli, short stature, and additional dysmorphic features without joint contractures. Iliac crest biopsy after alendronate treatment that improved her bone density revealed low trabecular connectivity, abundant patchy osteoid, and active bone formation with widely-spaced tetracycline labels. Chromosome 22q11 deletion analysis for velocardiofacial syndrome, COL1A1 and COL1A2 sequencing for prevalent types of OI, and Sanger sequencing of LRP5, PPIB, FKBP10, and IFITM5 for rare pediatric osteoporoses were negative. Copy number microarray excluded a contiguous gene syndrome. Instead, exome sequencing revealed two missense variants in PLOD2 which encodes procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (lysyl hydroxylase 2, LH2); exon 8, c.797G>T, p.Gly266Val (paternal), and exon 12, c.1280A>G, p.Asn427Ser (maternal). In the Exome Aggregation Consortium (ExAC) database, low frequency (Gly266Val, 0.0000419) and absence (Asn427Ser) implicated both variants as mutations of PLOD2. The father, mother, and sister (who carried the exon 12 defect) were reportedly well with normal parental DXA findings. BRKS2, characterized by under-hydroxylation of type I collagen telopeptides compromising their crosslinking, has been reported in at least 16 probands/families. Most PLOD2 mutations involve exons 17–19 (of 20 total) encoding the C-terminal domain with LH activity. However, truncating defects (nonsense, frameshift, splice site mutations) are also found throughout PLOD2. In three reports, AR PLOD2 mutations are not associated with congenital contractures. Our patient's missense defects lie within the central domain of unknown function of PLOD2. In our patient, compound heterozygosity with PLOD2 mutations is associated with a clinical phenotype distinctive from classic BRKS2 indicating that when COL1A1 and COL1A2 mutation testing is negative for OI without congenital contractures or pterygia, atypical BRKS should be considered.
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absence of FKBP10 in recessive type xi osteogenesis imperfecta leads to diminished collagen cross linking and reduced collagen deposition in extracellular matrix
Human Mutation, 2012Co-Authors: Aileen M Barnes, Maryann Weis, Wayne A Cabral, Edward L Mertz, Elena Makareeva, Sergey Leikin, David R Eyre, Carlos Trujillo, Joan C MariniAbstract:Recessive osteogenesis imperfecta (OI) is caused by defects in genes whose products interact with type I collagen for modification and/or folding. We identified a Palestinian pedigree with moderate and lethal forms of recessive OI caused by mutations in FKBP10 or PPIB, which encode endoplasmic reticulum resident chaperone/isomerases FKBP65 and CyPB, respectively. In one pedigree branch, both parents carry a deletion in PPIB (c.563_566delACAG), causing lethal type IX OI in their two children. In another branch, a child with moderate type XI OI has a homozygous FKBP10 mutation (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and FKBP65 protein is absent from proband cells. Proband collagen electrophoresis reveals slight band broadening, compatible with ≈10% overmodification. Normal chain incorporation, helix folding, and collagen Tm support a minimal general collagen chaperone role for FKBP65. However, there is a dramatic decrease in collagen deposited in culture despite normal collagen secretion. Mass spectrometry reveals absence of hydroxylation of the collagen telopeptide lysine involved in cross-linking, suggesting that FKBP65 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase. Proband collagen to organics ratio in matrix is approximately 30% of normal in Raman spectra. Immunofluorescence shows sparse, disorganized collagen fibrils in proband matrix. Hum Mutat 33:1589–1598, 2012. Published 2012 Wiley Periodicals, Inc.*
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New perspectives on osteogenesis imperfecta
Nature Reviews Endocrinology, 2011Co-Authors: Antonella Forlino, Aileen M Barnes, Wayne A Cabral, Joan C MariniAbstract:Osteogenesis imperfecta, or 'brittle bone disease', is a clinically heterogeneous heritable connective tissue disorder, the causative defects of which are directly related to type I collagen. Human cases and murine models of osteogenesis imperfecta are providing insight into common pathways in dominant and recessive osteogenesis imperfecta, leading to the re-evaluation of its definition, classification and therapeutic approaches. A new paradigm has emerged for osteogenesis imperfecta as a collagen-related disorder. The more prevalent autosomal dominant forms of osteogenesis imperfecta are caused by primary defects in type I collagen, whereas autosomal recessive forms are caused by deficiency of proteins which interact with type I procollagen for post-translational modification and/or folding. Factors that contribute to the mechanism of dominant osteogenesis imperfecta include intracellular stress, disruption of interactions between collagen and noncollagenous proteins, compromised matrix structure, abnormal cell–cell and cell–matrix interactions and tissue mineralization. Recessive osteogenesis imperfecta is caused by deficiency of any of the three components of the collagen prolyl 3-hydroxylation complex. Absence of 3-hydroxylation is associated with increased modification of the collagen helix, consistent with delayed collagen folding. Other causes of recessive osteogenesis imperfecta include deficiency of the collagen chaperones FKBP10 or Serpin H1. Murine models are crucial to uncovering the common pathways in dominant and recessive osteogenesis imperfecta bone dysplasia. Clinical management of osteogenesis imperfecta is multidisciplinary, encompassing substantial progress in physical rehabilitation and surgical procedures, management of hearing, dental and pulmonary abnormalities, as well as drugs, such as bisphosphonates and recombinant human growth hormone. Novel treatments using cell therapy or new drug regimens hold promise for the future. Osteogenesis imperfecta is a collagen-related disorder characterized by low bone mass, decreased bone strength and increased bone fragility Dominant osteogenesis imperfecta is caused by defects in the quantity or structure of type I procollagen, which affects bone at multiple levels, for example, matrix structure and mineralization Recessive osteogenesis imperfecta is caused by deficiency of proteins that interact with collagen and affect its post-translational modification or folding, such as CRTAP, P3H1 and PPIB and Serpin H1 and FKBP10 Common features of dominant and recessive osteogenesis imperfecta, for example, delayed collagen folding, effects on bone and cartilage or increased endoplasmic reticulum stress, may be the key to understanding its pathogenesis Clinical management of osteogenesis imperfecta should involve a multidisciplinary team that provides physical rehabilitation, genetic, hearing, dental, neurological, endocrine and surgical management Bisphosphonates are widely administered to individuals with osteogenesis imperfecta, with positive effects on bone mass and vertebral geometry, but cause a decline in bone material quality
Aileen M Barnes - One of the best experts on this subject based on the ideXlab platform.
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Bruck syndrome 2 variant lacking congenital contractures and involving a novel compound heterozygous PLOD2 mutation.
Bone, 2019Co-Authors: Steven Mumm, Aileen M Barnes, Gary S. Gottesman, Deborah Wenkert, Philippe M. Campeau, Angela Nenninger, Margaret Huskey, Vinieth N. Bijanki, Deborah J. Veis, Joan C MariniAbstract:Abstract Bruck syndrome (BRKS) is the rare disorder that features congenital joint contractures often with pterygia and subsequent fractures, early on called osteogenesis imperfecta (OI) type XI (OMIM # 610968 ). Its two forms, BRKS1 (OMIM # 259450 ) and BRKS2 (OMIM # 609220 ), reflect autosomal recessive (AR) inheritance of FKBP10 and PLOD2 loss-of-function mutations, respectively. A 10-year-old girl was referred with blue sclera, osteopenia, poorly-healing fragility fractures, Wormian skull bones, cleft soft palate, congenital fusion of cervical vertebrae, progressive scoliosis, bell-shaped thorax, restrictive and reactive pulmonary disease, protrusio acetabuli, short stature, and additional dysmorphic features without joint contractures. Iliac crest biopsy after alendronate treatment that improved her bone density revealed low trabecular connectivity, abundant patchy osteoid, and active bone formation with widely-spaced tetracycline labels. Chromosome 22q11 deletion analysis for velocardiofacial syndrome, COL1A1 and COL1A2 sequencing for prevalent types of OI, and Sanger sequencing of LRP5, PPIB, FKBP10, and IFITM5 for rare pediatric osteoporoses were negative. Copy number microarray excluded a contiguous gene syndrome. Instead, exome sequencing revealed two missense variants in PLOD2 which encodes procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (lysyl hydroxylase 2, LH2); exon 8, c.797G>T, p.Gly266Val (paternal), and exon 12, c.1280A>G, p.Asn427Ser (maternal). In the Exome Aggregation Consortium (ExAC) database, low frequency (Gly266Val, 0.0000419) and absence (Asn427Ser) implicated both variants as mutations of PLOD2. The father, mother, and sister (who carried the exon 12 defect) were reportedly well with normal parental DXA findings. BRKS2, characterized by under-hydroxylation of type I collagen telopeptides compromising their crosslinking, has been reported in at least 16 probands/families. Most PLOD2 mutations involve exons 17–19 (of 20 total) encoding the C-terminal domain with LH activity. However, truncating defects (nonsense, frameshift, splice site mutations) are also found throughout PLOD2. In three reports, AR PLOD2 mutations are not associated with congenital contractures. Our patient's missense defects lie within the central domain of unknown function of PLOD2. In our patient, compound heterozygosity with PLOD2 mutations is associated with a clinical phenotype distinctive from classic BRKS2 indicating that when COL1A1 and COL1A2 mutation testing is negative for OI without congenital contractures or pterygia, atypical BRKS should be considered.
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kuskokwim syndrome a recessive congenital contracture disorder extends the phenotype of FKBP10 mutations
Human Mutation, 2013Co-Authors: Aileen M Barnes, Geraldine Duncan, Maryann Weis, William Paton, Wayne A Cabral, Edward L Mertz, Elena Makareeva, Michael J Gambello, Felicitas Lacbawan, Sergey LeikinAbstract:Recessive mutations in FKBP10 at 17q21.2, encoding FKBP65, cause both osteogenesis imperfecta (OI) and Bruck syndrome (OI plus congenital contractures). Contractures are a variable manifestation of null/missense FKBP10 mutations. Kuskokwim syndrome (KS) is an autosomal recessive congenital contracture disorder found among Yup'ik Eskimos. Linkage mapping of KS to chromosome 17q21, together with contractures as a feature of FKBP10 mutations, made FKBP10 a candidate gene. We identified a homozygous three-nucleotide deletion in FKBP10 (c.877_879delTAC) in multiple Kuskokwim pedigrees; 3% of regional controls are carriers. The mutation deletes the highly conserved p.Tyr293 residue in FKBP65's third peptidyl-prolyl cis–trans isomerase domain. FKBP10 transcripts are normal, but mutant FKBP65 is destabilized to a residual 5%. Collagen synthesized by KS fibroblasts has substantially decreased hydroxylation of the telopeptide lysine crucial for collagen cross-linking, with 2%–10% hydroxylation in probands versus 60% in controls. Matrix deposited by KS fibroblasts has marked reduction in maturely cross-linked collagen. KS collagen is disorganized in matrix, and fibrils formed in vitro had subtle loosening of monomer packing. Our results imply that FKBP10 mutations affect collagen indirectly, by ablating FKBP65 support for collagen telopeptide hydroxylation by lysyl hydroxylase 2, thus decreasing collagen cross-links in tendon and bone matrix. FKBP10 mutations may also underlie other arthrogryposis syndromes.
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absence of FKBP10 in recessive type xi osteogenesis imperfecta leads to diminished collagen cross linking and reduced collagen deposition in extracellular matrix
Human Mutation, 2012Co-Authors: Aileen M Barnes, Maryann Weis, Wayne A Cabral, Edward L Mertz, Elena Makareeva, Sergey Leikin, David R Eyre, Carlos Trujillo, Joan C MariniAbstract:Recessive osteogenesis imperfecta (OI) is caused by defects in genes whose products interact with type I collagen for modification and/or folding. We identified a Palestinian pedigree with moderate and lethal forms of recessive OI caused by mutations in FKBP10 or PPIB, which encode endoplasmic reticulum resident chaperone/isomerases FKBP65 and CyPB, respectively. In one pedigree branch, both parents carry a deletion in PPIB (c.563_566delACAG), causing lethal type IX OI in their two children. In another branch, a child with moderate type XI OI has a homozygous FKBP10 mutation (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and FKBP65 protein is absent from proband cells. Proband collagen electrophoresis reveals slight band broadening, compatible with ≈10% overmodification. Normal chain incorporation, helix folding, and collagen Tm support a minimal general collagen chaperone role for FKBP65. However, there is a dramatic decrease in collagen deposited in culture despite normal collagen secretion. Mass spectrometry reveals absence of hydroxylation of the collagen telopeptide lysine involved in cross-linking, suggesting that FKBP65 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase. Proband collagen to organics ratio in matrix is approximately 30% of normal in Raman spectra. Immunofluorescence shows sparse, disorganized collagen fibrils in proband matrix. Hum Mutat 33:1589–1598, 2012. Published 2012 Wiley Periodicals, Inc.*
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Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix
Clinical Genetics, 2011Co-Authors: Maurizia Valli, Aileen M Barnes, Maryann Weis, Wayne A Cabral, Elena Makareeva, Sergey Leikin, David R Eyre, Angelo Gallanti, Simona Viglio, Franco AntoniazziAbstract:Osteogenesis imperfecta (OI) is a heterogeneous heritable connective tissue disorder characterized by bone fragility and deformity. The majority of OI cases have dominant inheritance (Sillence types I to IV OI) and result from mutations in the COL1A1 or COL1A2 genes, encoding the proα1(I) and proα2(I) chains of type I collagen, the major structural protein of bone (1, 2). Biochemically, collagen structural defects delay helical folding, exposing the chains to post-translational prolyl 4-hydroxylation and lysyl hydroxylation for a longer time, resulting in ‘over-modification’ and delayed electrophoretic migration of collagen chains. In the last 5 years, a few recessive forms of OI have been shown to be caused by defects in the genes encoding the components of the collagen prolyl 3-hydroxylation complex (3, 4): cartilage-associated protein (CRTAP) (type VII OI, OMIM #610682) (5, 6), LEPRE1 (7–9) (type VIII OI, OMIM #610915), and PPIB (10–12) (type IX OI, OMIM #259440). Recently, additional disease loci responsible for recessive OI have been identified: FKBP10 (13), SERPINH1 (14), SP7/OX (15), and SERPINF1 (16). While both FKBP10 and SERPINH1 code for collagen chaperones resident in the ER, products of the latter two genes instead are not directly involved in collagen production or secretion but are key factors in osteoblasts differentiation and activity. Patients with defects in the components of the ER-resident 3-hydroxylation complex have moderate to severe/lethal OI, with white sclerae, small to normal head circumference and structurally normal collagen. Loss-of-function mutations in CRTAP and LEPRE1 result in rhizomelia, decreased to absent 3-hydroxylation of α1(I)Pro986, and collagen helical overmodification indicative of delayed folding. Of the three components of the 3-hydroxylation complex, CRTAP is known to be secreted into the extracellular matrix (17, 18). Normally, about 10% of CRTAP is secreted, while most is retained in the ER in a complex with prolyl 3-hydroxylase 1 (P3H1). Sixteen CRTAP mutant alleles, occurring in 15 index probands, have been reported (5–7, 18–20). Most null cases are lethal in the perinatal period or within the first year of life. Five non-lethal cases have been described. We present here a 7-year-old Egyptian boy whose severe OI is caused by homozygosity for a frameshift mutation in CRTAP exon 1. His dermal fibroblast type I collagen has typical post-translational modification defects for type VII OI. We report here the novel finding that the collagen content of matrix deposited by patient cells in culture is severely decreased. This data is supported by an in vitro collagen matrix-chase assay. These investigations describe matrix deficiency and disorganization associated with CRTAP deficiency which may reflect the absence of the crucial functions of CRTAP in extracellular matrix.
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New perspectives on osteogenesis imperfecta
Nature Reviews Endocrinology, 2011Co-Authors: Antonella Forlino, Aileen M Barnes, Wayne A Cabral, Joan C MariniAbstract:Osteogenesis imperfecta, or 'brittle bone disease', is a clinically heterogeneous heritable connective tissue disorder, the causative defects of which are directly related to type I collagen. Human cases and murine models of osteogenesis imperfecta are providing insight into common pathways in dominant and recessive osteogenesis imperfecta, leading to the re-evaluation of its definition, classification and therapeutic approaches. A new paradigm has emerged for osteogenesis imperfecta as a collagen-related disorder. The more prevalent autosomal dominant forms of osteogenesis imperfecta are caused by primary defects in type I collagen, whereas autosomal recessive forms are caused by deficiency of proteins which interact with type I procollagen for post-translational modification and/or folding. Factors that contribute to the mechanism of dominant osteogenesis imperfecta include intracellular stress, disruption of interactions between collagen and noncollagenous proteins, compromised matrix structure, abnormal cell–cell and cell–matrix interactions and tissue mineralization. Recessive osteogenesis imperfecta is caused by deficiency of any of the three components of the collagen prolyl 3-hydroxylation complex. Absence of 3-hydroxylation is associated with increased modification of the collagen helix, consistent with delayed collagen folding. Other causes of recessive osteogenesis imperfecta include deficiency of the collagen chaperones FKBP10 or Serpin H1. Murine models are crucial to uncovering the common pathways in dominant and recessive osteogenesis imperfecta bone dysplasia. Clinical management of osteogenesis imperfecta is multidisciplinary, encompassing substantial progress in physical rehabilitation and surgical procedures, management of hearing, dental and pulmonary abnormalities, as well as drugs, such as bisphosphonates and recombinant human growth hormone. Novel treatments using cell therapy or new drug regimens hold promise for the future. Osteogenesis imperfecta is a collagen-related disorder characterized by low bone mass, decreased bone strength and increased bone fragility Dominant osteogenesis imperfecta is caused by defects in the quantity or structure of type I procollagen, which affects bone at multiple levels, for example, matrix structure and mineralization Recessive osteogenesis imperfecta is caused by deficiency of proteins that interact with collagen and affect its post-translational modification or folding, such as CRTAP, P3H1 and PPIB and Serpin H1 and FKBP10 Common features of dominant and recessive osteogenesis imperfecta, for example, delayed collagen folding, effects on bone and cartilage or increased endoplasmic reticulum stress, may be the key to understanding its pathogenesis Clinical management of osteogenesis imperfecta should involve a multidisciplinary team that provides physical rehabilitation, genetic, hearing, dental, neurological, endocrine and surgical management Bisphosphonates are widely administered to individuals with osteogenesis imperfecta, with positive effects on bone mass and vertebral geometry, but cause a decline in bone material quality
Wayne A Cabral - One of the best experts on this subject based on the ideXlab platform.
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kuskokwim syndrome a recessive congenital contracture disorder extends the phenotype of FKBP10 mutations
Human Mutation, 2013Co-Authors: Aileen M Barnes, Geraldine Duncan, Maryann Weis, William Paton, Wayne A Cabral, Edward L Mertz, Elena Makareeva, Michael J Gambello, Felicitas Lacbawan, Sergey LeikinAbstract:Recessive mutations in FKBP10 at 17q21.2, encoding FKBP65, cause both osteogenesis imperfecta (OI) and Bruck syndrome (OI plus congenital contractures). Contractures are a variable manifestation of null/missense FKBP10 mutations. Kuskokwim syndrome (KS) is an autosomal recessive congenital contracture disorder found among Yup'ik Eskimos. Linkage mapping of KS to chromosome 17q21, together with contractures as a feature of FKBP10 mutations, made FKBP10 a candidate gene. We identified a homozygous three-nucleotide deletion in FKBP10 (c.877_879delTAC) in multiple Kuskokwim pedigrees; 3% of regional controls are carriers. The mutation deletes the highly conserved p.Tyr293 residue in FKBP65's third peptidyl-prolyl cis–trans isomerase domain. FKBP10 transcripts are normal, but mutant FKBP65 is destabilized to a residual 5%. Collagen synthesized by KS fibroblasts has substantially decreased hydroxylation of the telopeptide lysine crucial for collagen cross-linking, with 2%–10% hydroxylation in probands versus 60% in controls. Matrix deposited by KS fibroblasts has marked reduction in maturely cross-linked collagen. KS collagen is disorganized in matrix, and fibrils formed in vitro had subtle loosening of monomer packing. Our results imply that FKBP10 mutations affect collagen indirectly, by ablating FKBP65 support for collagen telopeptide hydroxylation by lysyl hydroxylase 2, thus decreasing collagen cross-links in tendon and bone matrix. FKBP10 mutations may also underlie other arthrogryposis syndromes.
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absence of FKBP10 in recessive type xi osteogenesis imperfecta leads to diminished collagen cross linking and reduced collagen deposition in extracellular matrix
Human Mutation, 2012Co-Authors: Aileen M Barnes, Maryann Weis, Wayne A Cabral, Edward L Mertz, Elena Makareeva, Sergey Leikin, David R Eyre, Carlos Trujillo, Joan C MariniAbstract:Recessive osteogenesis imperfecta (OI) is caused by defects in genes whose products interact with type I collagen for modification and/or folding. We identified a Palestinian pedigree with moderate and lethal forms of recessive OI caused by mutations in FKBP10 or PPIB, which encode endoplasmic reticulum resident chaperone/isomerases FKBP65 and CyPB, respectively. In one pedigree branch, both parents carry a deletion in PPIB (c.563_566delACAG), causing lethal type IX OI in their two children. In another branch, a child with moderate type XI OI has a homozygous FKBP10 mutation (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and FKBP65 protein is absent from proband cells. Proband collagen electrophoresis reveals slight band broadening, compatible with ≈10% overmodification. Normal chain incorporation, helix folding, and collagen Tm support a minimal general collagen chaperone role for FKBP65. However, there is a dramatic decrease in collagen deposited in culture despite normal collagen secretion. Mass spectrometry reveals absence of hydroxylation of the collagen telopeptide lysine involved in cross-linking, suggesting that FKBP65 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase. Proband collagen to organics ratio in matrix is approximately 30% of normal in Raman spectra. Immunofluorescence shows sparse, disorganized collagen fibrils in proband matrix. Hum Mutat 33:1589–1598, 2012. Published 2012 Wiley Periodicals, Inc.*
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Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix
Clinical Genetics, 2011Co-Authors: Maurizia Valli, Aileen M Barnes, Maryann Weis, Wayne A Cabral, Elena Makareeva, Sergey Leikin, David R Eyre, Angelo Gallanti, Simona Viglio, Franco AntoniazziAbstract:Osteogenesis imperfecta (OI) is a heterogeneous heritable connective tissue disorder characterized by bone fragility and deformity. The majority of OI cases have dominant inheritance (Sillence types I to IV OI) and result from mutations in the COL1A1 or COL1A2 genes, encoding the proα1(I) and proα2(I) chains of type I collagen, the major structural protein of bone (1, 2). Biochemically, collagen structural defects delay helical folding, exposing the chains to post-translational prolyl 4-hydroxylation and lysyl hydroxylation for a longer time, resulting in ‘over-modification’ and delayed electrophoretic migration of collagen chains. In the last 5 years, a few recessive forms of OI have been shown to be caused by defects in the genes encoding the components of the collagen prolyl 3-hydroxylation complex (3, 4): cartilage-associated protein (CRTAP) (type VII OI, OMIM #610682) (5, 6), LEPRE1 (7–9) (type VIII OI, OMIM #610915), and PPIB (10–12) (type IX OI, OMIM #259440). Recently, additional disease loci responsible for recessive OI have been identified: FKBP10 (13), SERPINH1 (14), SP7/OX (15), and SERPINF1 (16). While both FKBP10 and SERPINH1 code for collagen chaperones resident in the ER, products of the latter two genes instead are not directly involved in collagen production or secretion but are key factors in osteoblasts differentiation and activity. Patients with defects in the components of the ER-resident 3-hydroxylation complex have moderate to severe/lethal OI, with white sclerae, small to normal head circumference and structurally normal collagen. Loss-of-function mutations in CRTAP and LEPRE1 result in rhizomelia, decreased to absent 3-hydroxylation of α1(I)Pro986, and collagen helical overmodification indicative of delayed folding. Of the three components of the 3-hydroxylation complex, CRTAP is known to be secreted into the extracellular matrix (17, 18). Normally, about 10% of CRTAP is secreted, while most is retained in the ER in a complex with prolyl 3-hydroxylase 1 (P3H1). Sixteen CRTAP mutant alleles, occurring in 15 index probands, have been reported (5–7, 18–20). Most null cases are lethal in the perinatal period or within the first year of life. Five non-lethal cases have been described. We present here a 7-year-old Egyptian boy whose severe OI is caused by homozygosity for a frameshift mutation in CRTAP exon 1. His dermal fibroblast type I collagen has typical post-translational modification defects for type VII OI. We report here the novel finding that the collagen content of matrix deposited by patient cells in culture is severely decreased. This data is supported by an in vitro collagen matrix-chase assay. These investigations describe matrix deficiency and disorganization associated with CRTAP deficiency which may reflect the absence of the crucial functions of CRTAP in extracellular matrix.
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New perspectives on osteogenesis imperfecta
Nature Reviews Endocrinology, 2011Co-Authors: Antonella Forlino, Aileen M Barnes, Wayne A Cabral, Joan C MariniAbstract:Osteogenesis imperfecta, or 'brittle bone disease', is a clinically heterogeneous heritable connective tissue disorder, the causative defects of which are directly related to type I collagen. Human cases and murine models of osteogenesis imperfecta are providing insight into common pathways in dominant and recessive osteogenesis imperfecta, leading to the re-evaluation of its definition, classification and therapeutic approaches. A new paradigm has emerged for osteogenesis imperfecta as a collagen-related disorder. The more prevalent autosomal dominant forms of osteogenesis imperfecta are caused by primary defects in type I collagen, whereas autosomal recessive forms are caused by deficiency of proteins which interact with type I procollagen for post-translational modification and/or folding. Factors that contribute to the mechanism of dominant osteogenesis imperfecta include intracellular stress, disruption of interactions between collagen and noncollagenous proteins, compromised matrix structure, abnormal cell–cell and cell–matrix interactions and tissue mineralization. Recessive osteogenesis imperfecta is caused by deficiency of any of the three components of the collagen prolyl 3-hydroxylation complex. Absence of 3-hydroxylation is associated with increased modification of the collagen helix, consistent with delayed collagen folding. Other causes of recessive osteogenesis imperfecta include deficiency of the collagen chaperones FKBP10 or Serpin H1. Murine models are crucial to uncovering the common pathways in dominant and recessive osteogenesis imperfecta bone dysplasia. Clinical management of osteogenesis imperfecta is multidisciplinary, encompassing substantial progress in physical rehabilitation and surgical procedures, management of hearing, dental and pulmonary abnormalities, as well as drugs, such as bisphosphonates and recombinant human growth hormone. Novel treatments using cell therapy or new drug regimens hold promise for the future. Osteogenesis imperfecta is a collagen-related disorder characterized by low bone mass, decreased bone strength and increased bone fragility Dominant osteogenesis imperfecta is caused by defects in the quantity or structure of type I procollagen, which affects bone at multiple levels, for example, matrix structure and mineralization Recessive osteogenesis imperfecta is caused by deficiency of proteins that interact with collagen and affect its post-translational modification or folding, such as CRTAP, P3H1 and PPIB and Serpin H1 and FKBP10 Common features of dominant and recessive osteogenesis imperfecta, for example, delayed collagen folding, effects on bone and cartilage or increased endoplasmic reticulum stress, may be the key to understanding its pathogenesis Clinical management of osteogenesis imperfecta should involve a multidisciplinary team that provides physical rehabilitation, genetic, hearing, dental, neurological, endocrine and surgical management Bisphosphonates are widely administered to individuals with osteogenesis imperfecta, with positive effects on bone mass and vertebral geometry, but cause a decline in bone material quality
Yuqing Chen - One of the best experts on this subject based on the ideXlab platform.
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FKBP10 deletion in osteoblasts leads to qualitative defects in bone
Journal of Bone and Mineral Research, 2017Co-Authors: Caressa Lietman, Yuqing Chen, Ingo Grafe, Hao Ding, Xiaohong Bi, Catherine G Ambrose, Nadja Fratzlzelman, Paul Roschger, Klaus Klaushofer, Wolfgang WagermaierAbstract:: Osteogenesis imperfecta (OI), also known as brittle bone disease, displays a spectrum of clinical severity from mild (OI type I) to severe early lethality (OI type II), with clinical features including low bone mass, fractures, and deformities. Mutations in the FK506 Binding Protein 10 (FKBP10), gene encoding the 65-kDa protein FKBP65, cause a recessive form of OI and Bruck syndrome, the latter being characterized by joint contractures in addition to low bone mass. We previously showed that FKBP10 expression is limited to bone, tendon, and ligaments in postnatal tissues. Furthermore, in both patients and FKBP10 knockout mice, collagen telopeptide hydroxylysine crosslinking is dramatically reduced. To further characterize the bone specific contributions of FKBP10, we conditionally ablated FKBP65 in FKBP10fl/fl mice (Mus musculus; C57BL/6) using the osteoblast-specific Col1a1 2.3-kb Cre recombinase. Using μCT, histomorphometry and quantitative backscattered electron imaging, we found minimal alterations in the quantity of bone and no differences in the degree of bone matrix mineralization in this model. However, mass spectroscopy (MS) of bone collagen demonstrated a decrease in mature, hydroxylysine-aldehyde crosslinking. Furthermore, bone of mutant mice exhibits a reduction in mineral-to-matrix ratio and in crystal size as shown by Raman spectroscopy and small-angle X-ray scattering, respectively. Importantly, abnormalities in bone quality were associated with impaired bone biomechanical strength in mutant femurs compared with those of wild-type littermates. Taken together, these data suggest that the altered collagen crosslinking through FKBP10 ablation in osteoblasts primarily leads to a qualitative defect in the skeleton. © 2017 American Society for Bone and Mineral Research.
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connective tissue alterations in FKBP10 mice
Human Molecular Genetics, 2014Co-Authors: Caressa Lietman, Abbhirami Rajagopal, Erica P Homan, Elda Munivez, Ming Ming Jiang, Terry Bertin, Yuqing Chen, John HicksAbstract:: Osteogenesis imperfecta (OI) is an inherited brittle bone disorder characterized by bone fragility and low bone mass. Loss of function mutations in FK506-binding protein 10 (FKBP10), encoding the FKBP65 protein, result in recessive OI and Bruck syndrome, of which the latter is additionally characterized by joint contractures. FKBP65 is thought to act as a collagen chaperone, but it is unknown how loss of FKBP65 affects collagen synthesis and extracellular matrix formation. We evaluated the developmental and postnatal expression of FKBP10 and analyzed the consequences of its generalized loss of function. FKBP10 is expressed at low levels in E13.5 mouse embryos, particularly in skeletal tissues, and steadily increases through E17.5 with expression in not only skeletal tissues, but also in visceral tissues. Postnatally, expression is limited to developing bone and ligaments. In contrast to humans, with complete loss of function mutations, FKBP10(-/-) mice do not survive birth, and embryos present with growth delay and tissue fragility. Type I calvarial collagen isolated from these mice showed reduced stable crosslink formation at telopeptide lysines. Furthermore, FKBP10(-/-) mouse embryonic fibroblasts show retention of procollagen in the cell layer and associated dilated endoplasmic reticulum. These data suggest a requirement for FKBP65 function during embryonic connective tissue development in mice, but the restricted expression postnatally in bone, ligaments and tendons correlates with the bone fragility and contracture phenotype in humans.
Claudia A Staabweijnitz - One of the best experts on this subject based on the ideXlab platform.
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fk506 binding protein 10 FKBP10 regulates lung fibroblast migration via collagen vi synthesis
Respiratory Research, 2018Co-Authors: Larissa Knuppel, Katharina Heinzelmann, R. Hatz, Oliver Eickelberg, Michael Lindner, J Behr, Claudia A StaabweijnitzAbstract:In idiopathic pulmonary fibrosis (IPF), fibroblasts gain a more migratory phenotype and excessively secrete extracellular matrix (ECM), ultimately leading to alveolar scarring and progressive dyspnea. Here, we analyzed the effects of deficiency of FK506-binding protein 10 (FKBP10), a potential IPF drug target, on primary human lung fibroblast (phLF) adhesion and migration. Using siRNA, FKBP10 expression was inhibited in phLF in absence or presence of 2ng/ml transforming growth factor-β1 (TGF-β1) and 0.1mM 2-phosphoascorbate. Effects on cell adhesion and migration were monitored by an immunofluorescence (IF)-based attachment assay, a conventional scratch assay, and single cell tracking by time-lapse microscopy. Effects on expression of key players in adhesion dynamics and migration were analyzed by qPCR and Western Blot. Colocalization was evaluated by IF microscopy and by proximity ligation assays. FKBP10 knockdown significantly attenuated adhesion and migration of phLF. Expression of collagen VI was decreased, while expression of key components of the focal adhesion complex was mostly upregulated. The effects on migration were 2-phosphoascorbate-dependent, suggesting collagen synthesis as the underlying mechanism. FKBP10 colocalized with collagen VI and coating culture dishes with collagen VI, and to a lesser extent with collagen I, abolished the effect of FKBP10 deficiency on migration. These findings show, to our knowledge for the first time, that FKBP10 interacts with collagen VI and that deficiency of FKBP10 reduces phLF migration mainly by downregulation of collagen VI synthesis. The results strengthen FKBP10 as an important intracellular regulator of ECM remodeling and support the concept of FKBP10 as drug target in IPF.
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a novel antifibrotic mechanism of nintedanib and pirfenidone inhibition of collagen fibril assembly
American Journal of Respiratory Cell and Molecular Biology, 2017Co-Authors: Larissa Knuppel, Juergen Behr, Katharina Heinzelmann, Yoshihiro Ishikawa, R. Hatz, Oliver Eickelberg, Hans Peter Bachinger, Michaela Aichler, Axel Walch, Claudia A StaabweijnitzAbstract:Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix, in particular, collagens. Two IPF therapeutics, nintedanib and pirfenidone, decelerate lung function decline, but their underlying mechanisms of action are poorly understood. In this study, we sought to analyze their effects on collagen synthesis and maturation at important regulatory levels. Primary human fibroblasts from patients with IPF and healthy donors were treated with nintedanib (0.01–1.0 μM) or pirfenidone (100-1,000 μM) in the absence or presence of transforming growth factor-β1. Effects on collagen, fibronectin, FKBP10, and HSP47 expression, and collagen I and III secretion, were analyzed by quantitative polymerase chain reaction and Western blot. The appearance of collagen fibrils was monitored by scanning electron microscopy, and the kinetics of collagen fibril assembly was assessed using a light-scattering approach. In IPF fibroblasts, nintedanib reduced the expression of collagen I and V, ...