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Jacqueline T. Hecht - One of the best experts on this subject based on the ideXlab platform.
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Novel therapeutic interventions for Pseudoachondroplasia.
Bone, 2017Co-Authors: Karen L. Posey, Jacqueline T. HechtAbstract:Pseudoachondroplasia (PSACH), a severe short-limbed dwarfing condition, is associated with life-long joint pain and early onset osteoarthritis. PSACH is caused by mutations in cartilage oligomeric matrix protein (COMP), a pentameric matricellular protein expressed primarily in cartilage and other musculoskeletal tissues. Mutations in COMP diminish calcium binding and as a result perturb protein folding and export to the extracellular matrix. Mutant COMP is retained in the endoplasmic reticulum (ER) of growth plate chondrocytes resulting in massive intracellular COMP retention. COMP trapped in the ER builds an intracellular matrix network that may prevent the normal cellular clearance mechanisms. We have shown that accumulation of intracellular matrix in mutant-COMP (MT-COMP) mice stimulates intense unrelenting ER stress, inflammation and oxidative stress. This cytotoxic stress triggers premature death of growth plate chondrocytes limiting long-bone growth. Here, we review the mutant COMP pathologic mechanisms and anti-inflammatory/antioxidant therapeutic approaches to reduce ER stress. In MT-COMP mice, aspirin and resveratrol both dampen the mutant COMP chondrocyte phenotype by decreasing intracellular accumulation, chondrocyte death and inflammatory marker expression. This reduction in chondrocyte stress translates into an improvement in long-bone growth in the MT-COMP mice. Our efforts now move to translational studies targeted at reducing the clinical consequences of MT-COMP and painful sequelae associated with PSACH.
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Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology
Molecular therapy : the journal of the American Society of Gene Therapy, 2017Co-Authors: Karen L. Posey, Francoise Coustry, Alka C. Veerisetty, Mohammad G. Hossain, Danielle Gattis, Sheri L. Booten, Joseph L. Alcorn, Punit P. Seth, Jacqueline T. HechtAbstract:Mutations in cartilage oligomeric matrix protein cause Pseudoachondroplasia, a severe disproportionate short stature disorder. Mutant cartilage oligomeric matrix protein produces massive intracellular retention of cartilage oligomeric matrix protein, stimulating ER and oxidative stresses and inflammation, culminating in post-natal loss of growth plate chondrocytes, which compromises linear bone growth. Treatments for Pseudoachondroplasia are limited because cartilage is relatively avascular and considered inaccessible. Here we report successful delivery and treatment using antisense oligonucleotide technology in our transgenic Pseudoachondroplasia mouse model. We demonstrate delivery of human cartilage oligomeric matrix protein-specific antisense oligonucleotides to cartilage and reduction of cartilage oligomeric matrix protein expression, which largely alleviates Pseudoachondroplasia growth plate chondrocyte pathology. One antisense oligonucleotide reduced steady-state levels of cartilage oligomeric matrix protein mRNA and dampened intracellular retention of mutant cartilage oligomeric matrix protein, leading to a reduction of inflammatory markers and cell death and partial restoration of proliferation. This novel and exciting work demonstrates that antisense-based therapy is a viable approach for treating Pseudoachondroplasia and other human cartilage disorders.
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Pseudoachondroplasia and painful sequelae
American Journal of Medical Genetics Part A, 2015Co-Authors: Candace Gamble, Joanne Nguyen, S. Shahrukh Hashmi, Jacqueline T. HechtAbstract:Pseudoachondroplasia (PSACH) is a well-described autosomal dominant short limb dwarfing condition caused by mutations in the cartilage oligomeric matrix protein gene (COMP). The most debilitating complication of the disorder is joint pain starting in childhood, the extent and severity of which is poorly defined. The aim of this study was to fully assess the pain and identify additional clinical complications affecting those with PSACH. An online survey was distributed to individuals with PSACH. Of the 77 surveys analyzed, 83% reported chronic pain starting as early as the newborn period. Pain was most frequently reported in weight bearing joints including the knees, hips, and back, and significantly interfered with their overall quality of life. For pain relief, patients with PSACH used a wide variety of treatments. However, patients reported only a 60% resolution of pain with their current treatments. An increase in other comorbidities was not found, specifically osteoporosis was not increased. This study documents for the first time that pain is the most common presenting symptom in PSACH and is often overlooked until short stature becomes obvious. The recognition of chronic pain as one of the earliest manifestations of PSACH is important to allow for prompt diagnosis. © 2015 Wiley Periodicals, Inc.
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Pseudoachondroplasia comp translating from the bench to the bedside
Matrix Biology, 2014Co-Authors: Karen L. Posey, Joseph L. Alcorn, Jacqueline T. HechtAbstract:Pseudoachondroplasia (PSACH) is a skeletal dysplasia characterized by disproportionate short stature, small hands and feet, abnormal joints and early onset osteoarthritis. PSACH is caused by mutations in thrombospondin-5 (TSP-5, also known as cartilage oligomeric matrix protein or COMP), a pentameric extracellular matrix protein primarily expressed in chondrocytes and musculoskeletal tissues. The thrombospondin gene family is composed of matricellular proteins that associate with the extracellular matrix (ECM) and regulate processes in the matrix. Mutations in COMP interfere with calcium-binding, protein conformation and export to the extracellular matrix, resulting in inappropriate intracellular COMP retention. This accumulation of misfolded protein is cytotoxic and triggers premature death of chondrocytes during linear bone growth, leading to shortened long bones. Both in vitro and in vivo models have been employed to study the molecular processes underlying development of the PSACH pathology. Here, we compare the strengths and weaknesses of current mouse models of PSACH and discuss how the resulting phenotypes may be translated to clinical therapies.
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Pseudoachondroplasia/COMP — translating from the bench to the bedside
Matrix biology : journal of the International Society for Matrix Biology, 2014Co-Authors: Karen L. Posey, Joseph L. Alcorn, Jacqueline T. HechtAbstract:Pseudoachondroplasia (PSACH) is a skeletal dysplasia characterized by disproportionate short stature, small hands and feet, abnormal joints and early onset osteoarthritis. PSACH is caused by mutations in thrombospondin-5 (TSP-5, also known as cartilage oligomeric matrix protein or COMP), a pentameric extracellular matrix protein primarily expressed in chondrocytes and musculoskeletal tissues. The thrombospondin gene family is composed of matricellular proteins that associate with the extracellular matrix (ECM) and regulate processes in the matrix. Mutations in COMP interfere with calcium-binding, protein conformation and export to the extracellular matrix, resulting in inappropriate intracellular COMP retention. This accumulation of misfolded protein is cytotoxic and triggers premature death of chondrocytes during linear bone growth, leading to shortened long bones. Both in vitro and in vivo models have been employed to study the molecular processes underlying development of the PSACH pathology. Here, we compare the strengths and weaknesses of current mouse models of PSACH and discuss how the resulting phenotypes may be translated to clinical therapies.
Karen L. Posey - One of the best experts on this subject based on the ideXlab platform.
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Novel therapeutic interventions for Pseudoachondroplasia.
Bone, 2017Co-Authors: Karen L. Posey, Jacqueline T. HechtAbstract:Pseudoachondroplasia (PSACH), a severe short-limbed dwarfing condition, is associated with life-long joint pain and early onset osteoarthritis. PSACH is caused by mutations in cartilage oligomeric matrix protein (COMP), a pentameric matricellular protein expressed primarily in cartilage and other musculoskeletal tissues. Mutations in COMP diminish calcium binding and as a result perturb protein folding and export to the extracellular matrix. Mutant COMP is retained in the endoplasmic reticulum (ER) of growth plate chondrocytes resulting in massive intracellular COMP retention. COMP trapped in the ER builds an intracellular matrix network that may prevent the normal cellular clearance mechanisms. We have shown that accumulation of intracellular matrix in mutant-COMP (MT-COMP) mice stimulates intense unrelenting ER stress, inflammation and oxidative stress. This cytotoxic stress triggers premature death of growth plate chondrocytes limiting long-bone growth. Here, we review the mutant COMP pathologic mechanisms and anti-inflammatory/antioxidant therapeutic approaches to reduce ER stress. In MT-COMP mice, aspirin and resveratrol both dampen the mutant COMP chondrocyte phenotype by decreasing intracellular accumulation, chondrocyte death and inflammatory marker expression. This reduction in chondrocyte stress translates into an improvement in long-bone growth in the MT-COMP mice. Our efforts now move to translational studies targeted at reducing the clinical consequences of MT-COMP and painful sequelae associated with PSACH.
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Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology
Molecular therapy : the journal of the American Society of Gene Therapy, 2017Co-Authors: Karen L. Posey, Francoise Coustry, Alka C. Veerisetty, Mohammad G. Hossain, Danielle Gattis, Sheri L. Booten, Joseph L. Alcorn, Punit P. Seth, Jacqueline T. HechtAbstract:Mutations in cartilage oligomeric matrix protein cause Pseudoachondroplasia, a severe disproportionate short stature disorder. Mutant cartilage oligomeric matrix protein produces massive intracellular retention of cartilage oligomeric matrix protein, stimulating ER and oxidative stresses and inflammation, culminating in post-natal loss of growth plate chondrocytes, which compromises linear bone growth. Treatments for Pseudoachondroplasia are limited because cartilage is relatively avascular and considered inaccessible. Here we report successful delivery and treatment using antisense oligonucleotide technology in our transgenic Pseudoachondroplasia mouse model. We demonstrate delivery of human cartilage oligomeric matrix protein-specific antisense oligonucleotides to cartilage and reduction of cartilage oligomeric matrix protein expression, which largely alleviates Pseudoachondroplasia growth plate chondrocyte pathology. One antisense oligonucleotide reduced steady-state levels of cartilage oligomeric matrix protein mRNA and dampened intracellular retention of mutant cartilage oligomeric matrix protein, leading to a reduction of inflammatory markers and cell death and partial restoration of proliferation. This novel and exciting work demonstrates that antisense-based therapy is a viable approach for treating Pseudoachondroplasia and other human cartilage disorders.
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Pseudoachondroplasia comp translating from the bench to the bedside
Matrix Biology, 2014Co-Authors: Karen L. Posey, Joseph L. Alcorn, Jacqueline T. HechtAbstract:Pseudoachondroplasia (PSACH) is a skeletal dysplasia characterized by disproportionate short stature, small hands and feet, abnormal joints and early onset osteoarthritis. PSACH is caused by mutations in thrombospondin-5 (TSP-5, also known as cartilage oligomeric matrix protein or COMP), a pentameric extracellular matrix protein primarily expressed in chondrocytes and musculoskeletal tissues. The thrombospondin gene family is composed of matricellular proteins that associate with the extracellular matrix (ECM) and regulate processes in the matrix. Mutations in COMP interfere with calcium-binding, protein conformation and export to the extracellular matrix, resulting in inappropriate intracellular COMP retention. This accumulation of misfolded protein is cytotoxic and triggers premature death of chondrocytes during linear bone growth, leading to shortened long bones. Both in vitro and in vivo models have been employed to study the molecular processes underlying development of the PSACH pathology. Here, we compare the strengths and weaknesses of current mouse models of PSACH and discuss how the resulting phenotypes may be translated to clinical therapies.
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Pseudoachondroplasia/COMP — translating from the bench to the bedside
Matrix biology : journal of the International Society for Matrix Biology, 2014Co-Authors: Karen L. Posey, Joseph L. Alcorn, Jacqueline T. HechtAbstract:Pseudoachondroplasia (PSACH) is a skeletal dysplasia characterized by disproportionate short stature, small hands and feet, abnormal joints and early onset osteoarthritis. PSACH is caused by mutations in thrombospondin-5 (TSP-5, also known as cartilage oligomeric matrix protein or COMP), a pentameric extracellular matrix protein primarily expressed in chondrocytes and musculoskeletal tissues. The thrombospondin gene family is composed of matricellular proteins that associate with the extracellular matrix (ECM) and regulate processes in the matrix. Mutations in COMP interfere with calcium-binding, protein conformation and export to the extracellular matrix, resulting in inappropriate intracellular COMP retention. This accumulation of misfolded protein is cytotoxic and triggers premature death of chondrocytes during linear bone growth, leading to shortened long bones. Both in vitro and in vivo models have been employed to study the molecular processes underlying development of the PSACH pathology. Here, we compare the strengths and weaknesses of current mouse models of PSACH and discuss how the resulting phenotypes may be translated to clinical therapies.
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Chop (Ddit3) Is Essential for D469del-COMP Retention and Cell Death in Chondrocytes in an Inducible Transgenic Mouse Model of Pseudoachondroplasia
The American journal of pathology, 2011Co-Authors: Karen L. Posey, Francoise Coustry, Alka C. Veerisetty, Joseph L. Alcorn, Peiman Liu, Jacqueline T. HechtAbstract:Cartilage oligomeric matrix protein (COMP), a secreted glycoprotein synthesized by chondrocytes, regulates proliferation and type II collagen assembly. Mutations in the COMP gene cause Pseudoachondroplasia and multiple epiphyseal dysplasia. Previously, we have shown that expression of D469del-COMP in transgenic mice causes intracellular retention of D469del-COMP, thereby recapitulating Pseudoachondroplasia chondrocyte pathology. This inducible transgenic D469del-COMP mouse is the only in vivo model to replicate the critical cellular and clinical features of Pseudoachondroplasia. Here, we report developmental studies of D469del-COMP-induced chondrocyte pathology from the prenatal period to adolescence. D469del-COMP retention was limited prenatally and did not negatively affect the growth plate until 3 weeks after birth. Results of immunostaining, transcriptome analysis, and qRT-PCR suggest a molecular model in which D469del-COMP triggers apoptosis during the first postnatal week. By 3 weeks (when most chondrocytes are retaining D469del-COMP), inflammation, oxidative stress, and DNA damage contribute to chondrocyte cell death by necroptosis. Importantly, by crossing the D469del-COMP mouse onto a Chop null background ( Ddit3 null), thereby eliminating Chop, the unfolded protein response was disrupted, thus alleviating both D469del-COMP intracellular retention and premature chondrocyte cell death. Chop therefore plays a significant role in processes that mediate D469del-COMP retention. Taken together, these results suggest that there may be an optimal window before the induction of significant D469del-COMP retention during which endoplasmic reticulum stress could be targeted.
Michelle Deere - One of the best experts on this subject based on the ideXlab platform.
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Identification of twelve mutations in cartilage oligomeric matrix protein (COMP) in patients with Pseudoachondroplasia
American journal of medical genetics, 1998Co-Authors: Michelle Deere, Heather L. Ferguson, Tiffany Sanford, Karla J. Daniels, Jacqueline T. HechtAbstract:Pseudoachondroplasia (PSACH) is an autosomal dominant dwarfing condition characterized by disproportionate short stature, joint laxity, and early-onset osteoarthrosis. PSACH is caused by mutations in the gene encoding cartilage oligomeric matrix protein (COMP). We are reporting on mutations in COMP in 12 patients with PSACH, including ten novel mutations. Eleven of the mutations are in exons 17A, 17B, and 18A, which encode the calcium-binding domains, and one mutation is in exon 19, which encodes part of the carboxy-terminal globular domain. Two of the mutations identified are the common delGAC(1430-1444) in exon 17B, which accounts for 36% of identified PSACH mutations. This report increases the range of mutations in COMP that cause PSACH and provides additional evidence for the importance of the calcium-binding domains and the globular domain to the function of COMP.
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Characterization of cartilage oligomeric matrix protein (COMP) in human normal and Pseudoachondroplasia musculoskeletal tissues.
Matrix biology : journal of the International Society for Matrix Biology, 1998Co-Authors: Jacqueline T. Hecht, Michelle Deere, William G. Cole, Elizabeth A. Putnam, Barbara M. Vertel, Hui Chen, Jack LawlerAbstract:Cartilage oligomeric matrix protein (COMP), the fifth member of the -thrombospondin gene family, is an extracellular matrix calcium-binding protein. The importance of COMP is underscored by the finding that mutations in COMP cause the human dwarfing condition, Pseudoachondroplasia (PSACH). Here, we report the results of human tissue distribution and cell secretion studies of human COMP. COMP is expressed and secreted by cultured monolayer chondrocyte, tendon and ligament cells, and COMP secretion is not restricted to a differentiated chondrocyte phenotype. Whereas COMP is retained in the endoplasmic reticulum that accumulates within PSACH chondrocytes in vivo, COMP is not retained intracellularly in the dedifferentiated PSACH chondrocytes in cultures. These results lend further support to the hypothesis that retention of COMP is related to the terminal PSACH chondrocyte phenotype, processing of proteins related to extracellular matrix formation, and maintenance in cartilage.
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Mosaicism in Pseudoachondroplasia.
American journal of medical genetics, 1997Co-Authors: Heather L. Ferguson, Michelle Deere, Judith G. Hall, Julie Rotta, Randall L. Evans, Jacqueline T. HechtAbstract:Pseudoachondroplasia (PSACH) is a spondylo-epi-metaphyseal dysplasia characterized by disproportionate short stature, generalized ligamentous laxity, and precocious osteoarthritis. PSACH is caused by mutations in the cartilage oligomeric matrix protein (COMP) gene, which codes for a noncollagenous protein expressed in the territorial matrix of chondrocytes. Autosomal dominant inheritance has been demonstrated in many families; however, autosomal recessive inheritance has been suggested in some severe familial cases. Alternatively, germline/somatic mosaicism has been proposed and is credible, since it has been shown that dominantly inherited and sporadic cases of PSACH are caused by the same genetic defect. Here, we present evidence demonstrating somatic mosaicism in two PSACH families that were originally considered to represent autosomal recessive inheritance. The results of this study suggest that autosomal recessive inheritance is unlikely and all cases of PSACH should be studied for mutations in COMP.
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Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause Pseudoachondroplasia.
Nature genetics, 1995Co-Authors: Jacqueline T. Hecht, Laura D. Nelson, Eric Crowder, Y. Wang, Frederick F.b. Elder, Wilbur Harrison, Clair A. Francomano, Christa Prange, Gregory G. Lennon, Michelle DeereAbstract:Pseudoachondroplasia (PSACH) is a well characterized dwarfing condition mapping to chromosome 19p12-13.1. Cartilage oligomeric matrix protein (COMP), a cartilage specific protein, maps to the same location within a contig that spans the PSACH locus. Using single strand conformation polymorphism (SSCP) analysis and nucleotide sequencing we have identified COMP mutations in eight familial and isolated PSACH cases. All mutations involve either a single base-pair change or a three base-pair deletion in exon 17B. Six mutations delete or change a well conserved aspartic acid residue within the calcium-binding type 3 repeats. These results demonstrate that mutations in the COMP gene cause pseudochondroplasia.
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linkage of typical Pseudoachondroplasia to chromosome 19
Genomics, 1993Co-Authors: Jacqueline T. Hecht, Michael D. Briggs, Michelle Deere, Clair Ann Francomano, Barbara Conner, William A. Horton, Matthew L. Warman, Daniel H. Cohn, Susan H. BlantonAbstract:Pseudoachondroplasia (PSACH) is an autosomal dominant dwarfing condition associated with disproportionate short stature, marked joint deformities, and early onset osteoarthritis. Previous linkage studies have excluded linkage to cartilage and noncartilagenous extracellular matrix candidate genes. Here, the authors report mapping the Pseudoachondroplasia gene to chromosome 19. Maximum lod scores of 4.70, 4.15, and 4.86 at [theta] = 0.00 were found for D19S212, D19S215, and D19S49, respectively. Multipoint analysis suggests the following order: D19S253-D19S199-(D19S212/PSACH/D19S215)-D19S222-D19S49. 24 refs., 4 figs., 1 tab.
Richard M Pauli - One of the best experts on this subject based on the ideXlab platform.
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Double heterozygosity in bone growth disorders: four new observations and review.
American journal of medical genetics. Part A, 2003Co-Authors: Maureen A Flynn, Richard M PauliAbstract:Because matings between individuals of small stature is common, information regarding double heterozygosity for dominantly inherited bone growth disorders is of considerable importance. We summarize seven occurrences of four combinations of double heterozygosity (achondroplasia/spondyloepiphyseal dysplasia congenita, achondroplasia/Pseudoachondroplasia, achondroplasia/osteogenesis imperfecta type I, achondroplasia/hypochondroplasia (non-FGFR3)), and review additional reports from the literature. Each of the eight different examples of double heterozygosity for bone growth disorders now reported results in distinct phenotypic features, differing severity, and disparate expectations. We document the natural history of each. The genetic processes underlying these disorders also are examined to assess whether knowledge of molecular mechanisms can be used to predict clinical severity.
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Double heterozygosity in bone growth disorders: Four new observations and review
American Journal of Medical Genetics Part A, 2003Co-Authors: Maureen A Flynn, Richard M PauliAbstract:Because matings between individuals of small stature is common, information regarding double heterozygosity for dominantly inherited bone growth disorders is of considerable importance. We summarize seven occurrences of four combinations of double heterozygosity (achondroplasia/spondyloe-piphyseal dysplasia congenita, achondroplasia/Pseudoachondroplasia, achondroplasia/ osteogenesis imperfecta type I, achondroplasia/hypochondroplasia (non-FGFR3)), and review additional reports from the literature. Each of the eight different examples of double heterozygosity for bone growth disorders now reported results in distinct phenotypic features, differing severity, and disparate expectations. We document the natural history of each. The genetic processes underlying these disorders also are examined to assess whether knowledge of molecular mechanisms can be used to predict clinical severity. 2003 Wiley-Liss, Inc.
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Analysis of the chondroitin sulfate proteoglycan core protein (CSPGCP) gene in achondroplasia and Pseudoachondroplasia.
American journal of human genetics, 1991Co-Authors: J. E. Finkelstein, Jacqueline T. Hecht, Richard M Pauli, K. Doege, Yoshihiko Yamada, Reed E. Pyeritz, John M. Graham, John B. Moeschler, Clair A. FrancomanoAbstract:Achondroplasia and Pseudoachondroplasia are autosomal dominant skeletal dysplasias resulting in short-limbed dwarfism. Histologic and ultrastructural studies of the cartilage in Pseudoachondroplasia and in homozygous achondroplasia have suggested a structural abnormality in chondroitin sulfate proteoglycan (CSPG), a major structural protein in the extra-cellular matrix. The gene encoding CSPG core protein (CSPGCP) is thus a logical "candidate gene" for analysis in these conditions. cDNA probes encoding CSPGCP were used to identify restriction fragment length polymorphisms (RFLPs) in DNA from a panel of control individuals. No gross alterations at the CSPGCP locus were noted in DNA from 37 individuals with achondroplasia and 5 individuals with Pseudoachondroplasia. In addition, allelic frequencies of the RFLPs were not significantly different among controls and patients with either condition. In one three-generation family with achondroplasia, close linkage of the CSPGCP locus and the skeletal dysplasia was excluded using a Bgl II polymorphism. Similarly, in a three-generation family with Pseudoachondroplasia, the CSPGCP gene was not tightly linked to the disease phenotype. These results indicate that mutations at the chondroitin sulfate proteoglycan core protein locus do not cause achondroplasia or Pseudoachondroplasia in these families.
Michael D. Briggs - One of the best experts on this subject based on the ideXlab platform.
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Pseudoachondroplasia and multiple epiphyseal dysplasia: Mutation review, molecular interactions, and genotype to phenotype correlations
Human mutation, 2002Co-Authors: Michael D. Briggs, K ChapmanAbstract:Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) constitute a bone dysplasia family, which is both genetically and phenotypically heterogeneous. The disease spectrum ranges from mild MED, which manifests with pain and stiffness in the joints and delayed and irregular ossification of the epiphyses, to the more severe PSACH, which is characterized by marked short stature, deformity of the legs, and ligamentous laxity. PSACH is almost exclusively caused by mutations in cartilage oligomeric matrix protein (COMP) whereas various forms of MED are caused by mutations in the genes encoding COMP, type IX collagen (COL9A1, COL9A2, and COL9A3), matrilin-3 (MATN3), and solute carrier member 26, member 2 gene (SLC26A2). In this review we discuss specific disease-causing mutations and the clustering of these mutations in functionally and structurally important regions of the respective gene products, genotype to phenotype correlations, and the diagnostic relevance of mutation screening in these osteochondrodysplasias.
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molecular diagnosis is important to confirm suspected Pseudoachondroplasia
Journal of Medical Genetics, 2000Co-Authors: Bill Newman, Dian Donnai, Michael D. BriggsAbstract:Editor—Pseudoachondroplasia (PSACH) is an autosomal dominant chondrodysplasia. In the majority of clinically defined cases, mutations have been identified in the gene encoding cartilage oligomeric matrix protein ( COMP ).1 Mutations in the COMP gene have also been identified in some forms of multiple epiphyseal dysplasia (MED), a related skeletal dysplasia.1 All of the mutations associated with PSACH and MED have been found in exons encoding the type III repeat region or C-terminal domain of COMP . Clinically, PSACH is characterised by short limbed dwarfism, which first becomes apparent in infancy, short fingers, ligamentous laxity, scoliosis, and early onset osteoarthritis (OA).2Radiographic features include small irregular epiphyses with delayed ossification, flared metaphyses, anterior beaking of the vertebral bodies, and delayed maturation of the triradiate cartilage and acetabulum.3 We report three patients who had previously been given erroneous diagnoses, in whom mutations in exon 13 of the COMP gene have been identified. This emphasises the utility of molecular diagnosis, particularly in adult patients where radiological diagnosis can be difficult. All three affected subjects were born to unaffected parents. Each was of normal intelligence and normal facial appearance. Case 1 presented at 5 years because of pain in both hips. Numerous diagnoses, including spondyloepiphyseal dysplasia congenita with coxa vara and Morquio's syndrome, were considered following x ray examination. Extensive surgery over the following years included a left femoral osteotomy and bilateral Girdlestones operations to treat her osteoarthritis. She has had two unaffected children. Examination at 65 years showed her height at 136 cm (<3rd centile), reduced …
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A large family with features of Pseudoachondroplasia and multiple epiphyseal dysplasia: exclusion of seven candidate gene loci that encode proteins of the cartilage extracellular matrix
Human Genetics, 1994Co-Authors: David L Rimoin, Michael D. Briggs, Matthew L. Warman, I. Merete Rasmussen, Peter J. Roughley, Helen E. Gruber, Bjorn R. Olsen, Y. Edward Hsia, Juliet Yuen, Kent ReinkerAbstract:We have identified a large family with a dominantly inherited chondrodysplasia characterized by a waddling gait, short limbs, and early onset osteoarthritis. The radiographic presentation resembles Pseudoachondroplasia in childhood and multiple epiphyseal dysplasia in adults. Electron microscopic examination of cartilage reveals accumulation of material within the rough endoplasmic reticulum similar to that seen in Pseudoachondroplasia and the Fairbank type of multiple epiphyseal dysplasia. By linkage analysis, we have excluded the genes for aggrecan, decorin, hexabrachion (tenascin), type II procollagen, the α1 chain of type XI procollagen, the α1 chain of type IX procollagen, and link protein, candidate genes that encode structural components of the cartilage extracellular matrix, as the disease locus for this disorder.
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linkage of typical Pseudoachondroplasia to chromosome 19
Genomics, 1993Co-Authors: Jacqueline T. Hecht, Michael D. Briggs, Michelle Deere, Clair Ann Francomano, Barbara Conner, William A. Horton, Matthew L. Warman, Daniel H. Cohn, Susan H. BlantonAbstract:Pseudoachondroplasia (PSACH) is an autosomal dominant dwarfing condition associated with disproportionate short stature, marked joint deformities, and early onset osteoarthritis. Previous linkage studies have excluded linkage to cartilage and noncartilagenous extracellular matrix candidate genes. Here, the authors report mapping the Pseudoachondroplasia gene to chromosome 19. Maximum lod scores of 4.70, 4.15, and 4.86 at [theta] = 0.00 were found for D19S212, D19S215, and D19S49, respectively. Multipoint analysis suggests the following order: D19S253-D19S199-(D19S212/PSACH/D19S215)-D19S222-D19S49. 24 refs., 4 figs., 1 tab.
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Linkage of Typical Pseudoachondroplasia to Chromosome 19
Genomics, 1993Co-Authors: Jacqueline T. Hecht, Michael D. Briggs, Michelle Deere, Clair Ann Francomano, Barbara Conner, William A. Horton, Matthew L. Warman, Daniel H. Cohn, Susan H. BlantonAbstract:Pseudoachondroplasia (PSACH) is an autosomal dominant dwarfing condition associated with disproportionate short stature, marked joint deformities, and early onset osteoarthritis. Previous linkage studies have excluded linkage to cartilage and noncartilagenous extracellular matrix candidate genes. Here, we report mapping the Pseudoachondroplasia gene to chromosome 19. Maximum lod scores of 4.70, 4.15, and 4.86 at theta = 0.00 were found for D19S212, D19S215, and D19S49, respectively. Multipoint analysis suggests the following order: D19S253-D19S199-(D19S212/PSACH/D19S215)-++ +D19S222-D19S49.
