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Takahiro Hamada - One of the best experts on this subject based on the ideXlab platform.
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the molecular basis of lipoid Proteinosis mutations in Extracellular Matrix Protein 1
Experimental Dermatology, 2007Co-Authors: I. Chan, Lu Liu, Takahiro Hamada, Gomathy Sethuraman, John A McgrathAbstract:Lipoid Proteinosis (OMIM 247100), also known as Urbach-Wiethe disease or hyalinosis cutis et mucosae, is a rare autosomal recessive disorder characterized by generalized thickening and scarring of the skin and mucosae. In 2002, the disorder was mapped to a locus on chromosome 1q21 and pathogenic mutations were identified in the ECM1 gene, which encodes for the glycoProtein Extracellular Matrix Protein 1 (ECM1). ECM1 has since been shown to have several important biological functions. It has a role in the structural organization of the dermis (binding to perlecan, Matrix metalloProteinase-9 and fibulin) as well as being targeted as an autoantigen in the acquired disease lichen sclerosus. ECM1 also shows over-expression in certain malignancies and is abnormally expressed in chronologically aged and photo-aged skin. Thus far, 26 different inherited mutations in ECM1 have been reported in lipoid Proteinosis. In this article, we provide an update on the molecular pathology of lipoid Proteinosis, including the addition of 15 new mutations in ECM1 to the mutation database, and review the biological functions of the ECM1 Protein in health and disease.
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autoantibodies to Extracellular Matrix Protein 1 in lichen sclerosus
The Lancet, 2003Co-Authors: Noritaka Oyama, I. Chan, Takahiro Hamada, Sallie Neill, Andrew P South, Vesarat Wessagowit, F Wojnarowska, David Dcruz, Graham J Hughes, M M BlackAbstract:Summary Background Lichen sclerosus is a common acquired inflammatory disorder of skin and mucous membranes. The aetiology is unknown, although HLA-subtype susceptibility and high rates of other autoimmune disorders suggest that autoantibodies to specific mucocutaneous antigens are involved. The clinicopathological similarities between lichen sclerosus and lipoid Proteinosis, which results from mutations in Extracellular Matrix Protein 1 (ECM1), suggest this Protein as an autoantigen. Methods We analysed serum autoantibody profiles in 171 individuals (86 with lichen sclerosus, 85 healthy controls) by immunoblotting of extracts from normal human skin and lipoid Proteinosis skin (lacking ECM1). We generated a full-length glutathione-S-transferase fusion Protein for ECM1 to confirm specific immunoreactivity. We affinity-purified serum from patients with lichen sclerosus and did indirect immunofluorescence microscopy on normal skin with or without preabsorption with recombinant ECM1. Findings By immunoblotting, IgG autoantibodies were found in 20 (67% [95% CI 45–84]) of 30 lichen sclerosus serum samples. The highest titre was 1 in 20. The bands were not detected in ECM1–deficient substrate. These samples, and those from 56 other patients with lichen sclerosus, showed immunoreactivity to the recombinant ECM1 Protein (64 of 86 positive; 74% [65–84]). Only six (7% [2–13]) of 85 control serum samples were positive. Affinity-purified IgG from serum of patients with lichen sclerosus labelled skin similarly to a polyclonal antibody to ECM1. The positive staining was blocked by preabsorption with excess recombinant ECM1 Protein. Interpretation These findings provide evidence for a specific humoral immune response to ECM1 in lichen sclerosus and offer insight into disease diagnosis, monitoring, and approaches to treatment.
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Extracellular Matrix Protein 1 gene ecm1 mutations in lipoid Proteinosis and genotype phenotype correlation
Journal of Investigative Dermatology, 2003Co-Authors: I. Chan, Takahiro Hamada, Noritaka Oyama, Andrew P South, Vesarat Wessagowit, G H S Ashton, Apatorn Siriwattana, Prachiya Jewhasuchin, S CharuwichitratanaAbstract:The autosomal recessive disorder lipoid Proteinosis results from mutations in Extracellular Matrix Protein 1 (ECM1), a glycoProtein expressed in several tissues (including skin) and composed of two alternatively spliced isoforms, ECM1a and ECM1b, the latter lacking exon 7 of this 10-exon gene (ECM1). To date, mutations that either affect ECM1a alone or perturb both ECM1 transcripts have been demonstrated in six cases. However, lipoid Proteinosis is clinically heterogeneous with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurological abnormalities such as temporal lobe epilepsy. In this study, we sequenced ECM1 in 10 further unrelated patients with lipoid Proteinosis to extend genotype-phenotype correlation and to add to the mutation database. We identified seven new homozygous nonsense or frameshift mutations: R53X (exon 3); 243delG (exon 4); 507delT (exon 6); 735delTG (exon 7); 785delA (exon 7); 892delC (exon 7) and 1190insC (exon 8), as well as two new compound heterozygous mutations: W160X/F167I (exon 6) and 542insAA/R243X (exons 6/7), none of which were found in controls. The mutation 507delT occurred in two unrelated subjects on different ECM1 haplotypes and may therefore represent a recurrent mutation in lipoid Proteinosis. Taken with the previously documented mutations in ECM1, this study supports the view that exons 6 and 7 are the most common sites for ECM1 mutations in lipoid Proteinosis. Clinically, it appears that mutations outside exon 7 are usually associated with a slightly more severe mucocutaneous lipoid Proteinosis phenotype, but neurological features do not show any specific genotype-phenotype correlation.
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lipoid Proteinosis maps to 1q21 and is caused by mutations in the Extracellular Matrix Protein 1 gene ecm1
Human Molecular Genetics, 2002Co-Authors: Takahiro Hamada, Andrew P South, G H S Ashton, W Irwin H Mclean, Michele Ramsay, Arti Nanda, Trefor Jenkins, Isobel Edelstein, Oliver Bleck, Vesarat WessagowitAbstract:Lipoid Proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease (OMIM 247100) is a rare, autosomal recessive disorder typified by generalized thickening of skin, mucosae and certain viscera. Classical features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. Histologically, there is widespread deposition of hyaline (glycoProtein) material and disruption/reduplication of basement membrane. The aetiology of LP is currently unknown. Using DNA from three affected siblings in a consanguineous Saudi Arabian family we performed genome-wide linkage and mapped the disorder to 1q21 (marker D1S498) with a two-point LOD score of 3.45 at theta = 0. A further 28 affected individuals from five other unrelated consanguineous family groups from different geographical regions also showed complete linkage and resulted in a maximum two-point LOD score of 21.85 at theta = 0. Using available markers in the interval between D1S442 and D1S305, the observed recombinants placed the gene in a 2.3 cM critical interval between D1S2344 and D1S2343 (Marshfield genetic map) corresponding to an approximately 6.5 Mb region on the UCSC physical map. Using a candidate gene approach (comparison of control versus LP gene expression in cultured fibroblasts) and subsequent direct sequencing of genomic DNA, we identified six different homozygous loss-of-function mutations in the Extracellular Matrix Protein 1 gene (ECM1). Although the precise function of ECM1 is not known, our findings provide the first clinical indication of its relevance to skin adhesion, epidermal differentiation, wound healing, scarring, angiogenesis/angiopathy and basement membrane physiology, as well as defining the molecular basis of this inherited disorder.
Yi Cao - One of the best experts on this subject based on the ideXlab platform.
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Modulating the Mechanical Stability of Extracellular Matrix Protein Tenascin-C in a Controlled and Reversible Fashion
Biophysical Journal, 2010Co-Authors: Shulin Zhuang, Qing Peng, Yi CaoAbstract:Tenascin-C is a large Extracellular Matrix Protein and is subject to stretching force under its physiological condition. Regulating the mechanical properties of the fibronectin type III domains of tenascin-C will alter its response to mechanical stretching force and thus may provide the possibility of regulating the biological activities of tenascin-C in living cells. However, tuning the mechanical stability of Proteins in a rational and systematic fashion remains challenging. Combining steered molecular dynamics simulations, Protein engineering and single-molecule atomic force microscopy, we have rationally engineered a bihistidine-based metal chelation site into the third fibronectin type III domain (TNfn3) of tenascin-C. We used its metal chelation capability to selectively increase the unfolding energy barrier for the rate-limiting step during the mechanical unfolding of TNfn3. The resultant TNfn3 mutant exhibits enhanced mechanical stability. Using a stronger metal chelator, one can convert TNfn3 back to a state of lower mechanical stability. This is the first step toward engineering Extracellular Matrix Proteins with defined mechanical properties, which can be modulated reversibly by external stimuli, and will provide the possibility of using external stimuli to regulate the biological functions of Extracellular Matrix Proteins.
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Modulating the mechanical stability of Extracellular Matrix Protein tenascin-C in a controlled and reversible fashion.
Journal of molecular biology, 2009Co-Authors: Shulin Zhuang, Qing Peng, Yi CaoAbstract:Stretching force can induce conformational changes of Proteins and is believed to be an important biological signal in the mechanotransduction network. Tenascin-C is a large Extracellular Matrix Protein and is subject to stretching force under its physiological condition. Regulating the mechanical properties of the fibronectin type III domains of tenascin-C will alter its response to mechanical stretching force and thus may provide the possibility of regulating the biological activities of tenascin-C in living cells. However, tuning the mechanical stability of Proteins in a rational and systematic fashion remains challenging. Using the third fibronectin type III domain (TNfn3) of tenascin-C as a model system, here we report a successful engineering of a mechanically stronger Extracellular Matrix Protein via engineered metal chelation. Combining steered molecular dynamics simulations, Protein engineering and single-molecule atomic force microscopy, we have rationally engineered a bihistidine-based metal chelation site into TNfn3. We used its metal chelation capability to selectively increase the unfolding energy barrier for the rate-limiting step during the mechanical unfolding of TNfn3. The resultant TNfn3 mutant exhibits enhanced mechanical stability. Using a stronger metal chelator, one can convert TNfn3 back to a state of lower mechanical stability. This is the first step toward engineering Extracellular Matrix Proteins with defined mechanical properties, which can be modulated reversibly by external stimuli, and will provide the possibility of using external stimuli to regulate the biological functions of Extracellular Matrix Proteins.
Vesarat Wessagowit - One of the best experts on this subject based on the ideXlab platform.
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autoantibodies to Extracellular Matrix Protein 1 in lichen sclerosus
The Lancet, 2003Co-Authors: Noritaka Oyama, I. Chan, Takahiro Hamada, Sallie Neill, Andrew P South, Vesarat Wessagowit, F Wojnarowska, David Dcruz, Graham J Hughes, M M BlackAbstract:Summary Background Lichen sclerosus is a common acquired inflammatory disorder of skin and mucous membranes. The aetiology is unknown, although HLA-subtype susceptibility and high rates of other autoimmune disorders suggest that autoantibodies to specific mucocutaneous antigens are involved. The clinicopathological similarities between lichen sclerosus and lipoid Proteinosis, which results from mutations in Extracellular Matrix Protein 1 (ECM1), suggest this Protein as an autoantigen. Methods We analysed serum autoantibody profiles in 171 individuals (86 with lichen sclerosus, 85 healthy controls) by immunoblotting of extracts from normal human skin and lipoid Proteinosis skin (lacking ECM1). We generated a full-length glutathione-S-transferase fusion Protein for ECM1 to confirm specific immunoreactivity. We affinity-purified serum from patients with lichen sclerosus and did indirect immunofluorescence microscopy on normal skin with or without preabsorption with recombinant ECM1. Findings By immunoblotting, IgG autoantibodies were found in 20 (67% [95% CI 45–84]) of 30 lichen sclerosus serum samples. The highest titre was 1 in 20. The bands were not detected in ECM1–deficient substrate. These samples, and those from 56 other patients with lichen sclerosus, showed immunoreactivity to the recombinant ECM1 Protein (64 of 86 positive; 74% [65–84]). Only six (7% [2–13]) of 85 control serum samples were positive. Affinity-purified IgG from serum of patients with lichen sclerosus labelled skin similarly to a polyclonal antibody to ECM1. The positive staining was blocked by preabsorption with excess recombinant ECM1 Protein. Interpretation These findings provide evidence for a specific humoral immune response to ECM1 in lichen sclerosus and offer insight into disease diagnosis, monitoring, and approaches to treatment.
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Extracellular Matrix Protein 1 gene ecm1 mutations in lipoid Proteinosis and genotype phenotype correlation
Journal of Investigative Dermatology, 2003Co-Authors: I. Chan, Takahiro Hamada, Noritaka Oyama, Andrew P South, Vesarat Wessagowit, G H S Ashton, Apatorn Siriwattana, Prachiya Jewhasuchin, S CharuwichitratanaAbstract:The autosomal recessive disorder lipoid Proteinosis results from mutations in Extracellular Matrix Protein 1 (ECM1), a glycoProtein expressed in several tissues (including skin) and composed of two alternatively spliced isoforms, ECM1a and ECM1b, the latter lacking exon 7 of this 10-exon gene (ECM1). To date, mutations that either affect ECM1a alone or perturb both ECM1 transcripts have been demonstrated in six cases. However, lipoid Proteinosis is clinically heterogeneous with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurological abnormalities such as temporal lobe epilepsy. In this study, we sequenced ECM1 in 10 further unrelated patients with lipoid Proteinosis to extend genotype-phenotype correlation and to add to the mutation database. We identified seven new homozygous nonsense or frameshift mutations: R53X (exon 3); 243delG (exon 4); 507delT (exon 6); 735delTG (exon 7); 785delA (exon 7); 892delC (exon 7) and 1190insC (exon 8), as well as two new compound heterozygous mutations: W160X/F167I (exon 6) and 542insAA/R243X (exons 6/7), none of which were found in controls. The mutation 507delT occurred in two unrelated subjects on different ECM1 haplotypes and may therefore represent a recurrent mutation in lipoid Proteinosis. Taken with the previously documented mutations in ECM1, this study supports the view that exons 6 and 7 are the most common sites for ECM1 mutations in lipoid Proteinosis. Clinically, it appears that mutations outside exon 7 are usually associated with a slightly more severe mucocutaneous lipoid Proteinosis phenotype, but neurological features do not show any specific genotype-phenotype correlation.
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lipoid Proteinosis maps to 1q21 and is caused by mutations in the Extracellular Matrix Protein 1 gene ecm1
Human Molecular Genetics, 2002Co-Authors: Takahiro Hamada, Andrew P South, G H S Ashton, W Irwin H Mclean, Michele Ramsay, Arti Nanda, Trefor Jenkins, Isobel Edelstein, Oliver Bleck, Vesarat WessagowitAbstract:Lipoid Proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease (OMIM 247100) is a rare, autosomal recessive disorder typified by generalized thickening of skin, mucosae and certain viscera. Classical features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. Histologically, there is widespread deposition of hyaline (glycoProtein) material and disruption/reduplication of basement membrane. The aetiology of LP is currently unknown. Using DNA from three affected siblings in a consanguineous Saudi Arabian family we performed genome-wide linkage and mapped the disorder to 1q21 (marker D1S498) with a two-point LOD score of 3.45 at theta = 0. A further 28 affected individuals from five other unrelated consanguineous family groups from different geographical regions also showed complete linkage and resulted in a maximum two-point LOD score of 21.85 at theta = 0. Using available markers in the interval between D1S442 and D1S305, the observed recombinants placed the gene in a 2.3 cM critical interval between D1S2344 and D1S2343 (Marshfield genetic map) corresponding to an approximately 6.5 Mb region on the UCSC physical map. Using a candidate gene approach (comparison of control versus LP gene expression in cultured fibroblasts) and subsequent direct sequencing of genomic DNA, we identified six different homozygous loss-of-function mutations in the Extracellular Matrix Protein 1 gene (ECM1). Although the precise function of ECM1 is not known, our findings provide the first clinical indication of its relevance to skin adhesion, epidermal differentiation, wound healing, scarring, angiogenesis/angiopathy and basement membrane physiology, as well as defining the molecular basis of this inherited disorder.
John W. Hollingsworth - One of the best experts on this subject based on the ideXlab platform.
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Retraction: "The Role of the Extracellular Matrix Protein Mindin in Airway Response to Environmental Airways Injury".
Environmental health perspectives, 2011Co-Authors: Sarah Frush, Erin N. Potts, Stavros Garantziotis, W. Michael Foster, John W. HollingsworthAbstract:Background: Our previous work demonstrated that the Extracellular Matrix Protein mindin contributes to allergic airways disease. However, the role of mindin in nonallergic airways disease has not p...
David A Cheresh - One of the best experts on this subject based on the ideXlab platform.
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vitronectin and its receptors
Current Opinion in Cell Biology, 1993Co-Authors: Brunhilde Feldinghabermann, David A ChereshAbstract:Abstract The Extracellular Matrix Protein vitronectin is recognized as an adhesive substrate by cells expressing at least one of four known vitronectin receptors: integrins αvβ1, αvβ3, αvβ5 or αIIbβ3. Cell interaction with vitronectin may induced spreading and migration and have an effect on cell growth and differentiation in specific processes, such as tumor growth and metastasis, wound healing, bone resorption and viral infection.
