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Monzur Murshed - One of the best experts on this subject based on the ideXlab platform.
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matrix gla Protein Deficiency impairs nasal septum growth causing midface hypoplasia
Journal of Biological Chemistry, 2017Co-Authors: Juliana Marulanda, Hazem Eimar, Michelle Berkvens, Hassem Roman, Teresa Borras, Mathieu Ferron, Faleh Tamimi, Marc D Mckee, Valentin Nelea, Monzur MurshedAbstract:Abstract Genetic and environmental factors may lead to abnormal growth of the orofacial skeleton affecting the overall structure of the face. In the current study, we investigated the craniofacial abnormalities in a mouse model for Keutel syndrome, a rare genetic disease caused by loss-of-function mutations in the matrix Gla Protein (MGP) gene. Keutel syndrome patients show diffuse ectopic calcification of cartilaginous tissues and impaired midface development. Our comparative cephalometric analyses of micro-CT images revealed a severe midface hypoplasia in Mgp-/- mice. In vivo reporter studies demonstrated that the Mgp promoter is highly active at the cranial sutures, cranial base synchondroses and nasal septum. While sutures and cranial base synchondroses showed normal anatomical features, the nasal septum was found to be abnormally mineralized and shortened in Mgp-/- mice. Transgenic restoration of Mgp expression in chondrocytes fully corrected the craniofacial anomalies caused by MGP Deficiency, suggesting a local role for MGP in the developing nasal septum. Although there was no upregulation of markers for hypertrophic chondrocytes, TUNEL assay showed a marked increase of apoptotic chondrocytes in the calcified nasal septum. Transmission electron microscopy confirmed unusual mineral deposits in the septal extracellular matrix (ECM) of the mutant mice. Of note, systemic reduction of inorganic phosphate level was sufficient to prevent nasal septum mineralization in Mgp-/-;Hyp compound mutants. Our work provides evidence that modulation of local and systemic factors regulating ECM mineralization can be possible therapeutic strategies to prevent ectopic cartilage calcification and some forms of congenital craniofacial anomalies in humans.
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matrix gla Protein Deficiency impairs nasal septum growth causing midface hypoplasia
Journal of Biological Chemistry, 2017Co-Authors: Juliana Marulanda, Hazem Eimar, Michelle Berkvens, Hassem Roman, Teresa Borras, Mathieu Ferron, Faleh Tamimi, Marc D Mckee, Valentin Nelea, Monzur MurshedAbstract:Genetic and environmental factors may lead to abnormal growth of the orofacial skeleton, affecting the overall structure of the face. In this study, we investigated the craniofacial abnormalities in a mouse model for Keutel syndrome, a rare genetic disease caused by loss-of-function mutations in the matrix Gla Protein (MGP) gene. Keutel syndrome patients show diffuse ectopic calcification of cartilaginous tissues and impaired midface development. Our comparative cephalometric analyses of micro-computed tomography images revealed a severe midface hypoplasia in Mgp−/− mice. In vivo reporter studies demonstrated that the Mgp promoter is highly active at the cranial sutures, cranial base synchondroses, and nasal septum. Interestingly, the cranial sutures of the mutant mice showed normal anatomical features. Although we observed a mild increase in mineralization of the spheno-occipital synchondrosis, it did not reduce the relative length of the cranial base in comparison with total skull length. Contrary to this, we found the nasal septum to be abnormally mineralized and shortened in Mgp−/− mice. Transgenic restoration of Mgp expression in chondrocytes fully corrected the craniofacial anomalies caused by MGP Deficiency, suggesting a local role for MGP in the developing nasal septum. Although there was no up-regulation of markers for hypertrophic chondrocytes, a TUNEL assay showed a marked increase in apoptotic chondrocytes in the calcified nasal septum. Transmission electron microscopy confirmed unusual mineral deposits in the septal extracellular matrix of the mutant mice. Of note, the systemic reduction of the inorganic phosphate level was sufficient to prevent abnormal mineralization of the nasal septum in Mgp−/−;Hyp compound mutants. Our work provides evidence that modulation of local and systemic factors regulating extracellular matrix mineralization can be possible therapeutic strategies to prevent ectopic cartilage calcification and some forms of congenital craniofacial anomalies in humans.
R. J. A. Wanders - One of the best experts on this subject based on the ideXlab platform.
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ether lipid biosynthesis alkyl dihydroxyacetonephosphate synthase Protein Deficiency leads to reduced dihydroxyacetonephosphate acyltransferase activities
Journal of Lipid Research, 1999Co-Authors: E. De Vet, Lodewijk Ijlst, W Oostheim, C Dekker, Hugo W Moser, R. J. A. WandersAbstract:Recent studies have indicated that two peroxisomal enzymes involved in ether lipid synthesis, i.e., dihydroxyacetonephosphate acyltransferase and alkyl-dihydroxyacetonephosphate synthase, are directed to peroxisomes by different targeting signals, i.e., peroxisomal targeting signal type 1 and type 2, respectively. In this study, we describe a new human fibroblast cell line in which alkyl-dihydroxyacetonephosphate synthase was found to be deficient both at the level of enzyme activity and enzyme Protein. At the cDNA level, a 128 base pair deletion was found leading to a premature stop. Remarkably, dihydroxyacetonephosphate acyltransferase activity was strongly reduced to a level comparable to the activities measured in fibroblasts from patients affected by the classical form of rhizomelic chondrodysplasia punctata (caused by a defect in peroxisomal targeting signal type 2 import). Dihydroxyacetonephosphate acyltransferase activity was completely normal in another alkyl-dihydroxyacetonephosphate synthase activity-deficient patient. Fibroblasts from this patient showed normal levels of the synthase Protein and inactivity results from a point mutation leading to an amino acid substitution. These results strongly suggest that the activity of dihydroxyacetonephosphate acyltransferase is dependent on the presence of alkyl-dihydroxyacetonephosphate synthase Protein. This interpretation implies that the Deficiency of dihydroxyacetonephosphate acyltransferase (targeted by a peroxisomal targeting signal type 1) in the classic form of rhizomelic chondrodysplasia punctata is a consequence of the absence of the alkyl-dihydroxyacetonephosphate synthase Protein (targeted by a peroxisomal targeting signal type 2).
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peroxisomal d hydroxyacyl coa dehydrogenase Deficiency resolution of the enzyme defect and its molecular basis in bifunctional Protein Deficiency
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: E G Van Grunsven, E Van Berkel, L Ijlst, P Vreken, J B C De Klerk, Jerzy Adamski, Hugh Lemonde, Peter E Clayton, Dean Cuebas, R. J. A. WandersAbstract:Peroxisomes play an essential role in a number of different metabolic pathways, including the β-oxidation of a distinct set of fatty acids and fatty acid derivatives. The importance of the peroxisomal β-oxidation system in humans is made apparent by the existence of a group of inherited diseases in which peroxisomal β-oxidation is impaired. This includes X-linked adrenoleukodystrophy and other disorders with a defined defect. On the other hand, many patients have been described with a defect in peroxisomal β-oxidation of unknown etiology. Resolution of the defects in these patients requires the elucidation of the enzymatic organization of the peroxisomal β-oxidation system. Importantly, a new peroxisomal β-oxidation enzyme was recently described called d-bifunctional Protein with enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activity primarily reacting with α-methyl fatty acids like pristanic acid and di- and trihydroxycholestanoic acid. In this patient we describe the first case of d-bifunctional Protein Deficiency as resolved by enzyme activity measurements and mutation analysis. The mutation found (Gly16Ser) is in the dehydrogenase coding part of the gene in an important loop of the Rossman fold forming the NAD+-binding site. The results show that the newly identified d-bifunctional Protein plays an essential role in the peroxisomal β-oxidation pathway that cannot be compensated for by the l-specific bifunctional Protein.
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human trifunctional Protein Deficiency a new disorder of mitochondrial fatty acid beta oxidation
Biochemical and Biophysical Research Communications, 1992Co-Authors: R. J. A. Wanders, Lodewijk Ijlst, Arnold Munnich, F Poggi, Jeanpaul Bonnefont, Michele Brivet, D Rabier, J M SaudubrayAbstract:Abstract In this paper we report the identification of a new disorder of mitochondrial fatty acid β-oxidation in a patient which presented with clear manifestations of a mitochondrial β-oxidation disorder. Subsequent studies in fibroblasts revealed an impairment in palmitate β-oxidation and in addition, a combined Deficiency of long-chain enoyl-CoA hydratase, longchain 3-hydroxyacyl-CoA-dehydrogenase and long-chain 3-oxoacyl-CoA thiolase. The recent identification of a multifunctional, membrane-bound 9-oxidation enzyme Protein catalyzing all these three enzyme activities (Carpenter et al. (1992) Biochem. Biophys. Res. Commun. 183, 443–448; Uchida et al. (1992) J. Biol. Chem. 267, 1034–1041) suggested an underlying basis for this peculiar combination of three enzyme deficiencies. We show by means of size-exclusion chromatography that there is, indeed, a Deficiency of the multifunctional β-oxidation enzyme Protein in this patient.
Juliana Marulanda - One of the best experts on this subject based on the ideXlab platform.
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matrix gla Protein Deficiency impairs nasal septum growth causing midface hypoplasia
Journal of Biological Chemistry, 2017Co-Authors: Juliana Marulanda, Hazem Eimar, Michelle Berkvens, Hassem Roman, Teresa Borras, Mathieu Ferron, Faleh Tamimi, Marc D Mckee, Valentin Nelea, Monzur MurshedAbstract:Abstract Genetic and environmental factors may lead to abnormal growth of the orofacial skeleton affecting the overall structure of the face. In the current study, we investigated the craniofacial abnormalities in a mouse model for Keutel syndrome, a rare genetic disease caused by loss-of-function mutations in the matrix Gla Protein (MGP) gene. Keutel syndrome patients show diffuse ectopic calcification of cartilaginous tissues and impaired midface development. Our comparative cephalometric analyses of micro-CT images revealed a severe midface hypoplasia in Mgp-/- mice. In vivo reporter studies demonstrated that the Mgp promoter is highly active at the cranial sutures, cranial base synchondroses and nasal septum. While sutures and cranial base synchondroses showed normal anatomical features, the nasal septum was found to be abnormally mineralized and shortened in Mgp-/- mice. Transgenic restoration of Mgp expression in chondrocytes fully corrected the craniofacial anomalies caused by MGP Deficiency, suggesting a local role for MGP in the developing nasal septum. Although there was no upregulation of markers for hypertrophic chondrocytes, TUNEL assay showed a marked increase of apoptotic chondrocytes in the calcified nasal septum. Transmission electron microscopy confirmed unusual mineral deposits in the septal extracellular matrix (ECM) of the mutant mice. Of note, systemic reduction of inorganic phosphate level was sufficient to prevent nasal septum mineralization in Mgp-/-;Hyp compound mutants. Our work provides evidence that modulation of local and systemic factors regulating ECM mineralization can be possible therapeutic strategies to prevent ectopic cartilage calcification and some forms of congenital craniofacial anomalies in humans.
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matrix gla Protein Deficiency impairs nasal septum growth causing midface hypoplasia
Journal of Biological Chemistry, 2017Co-Authors: Juliana Marulanda, Hazem Eimar, Michelle Berkvens, Hassem Roman, Teresa Borras, Mathieu Ferron, Faleh Tamimi, Marc D Mckee, Valentin Nelea, Monzur MurshedAbstract:Genetic and environmental factors may lead to abnormal growth of the orofacial skeleton, affecting the overall structure of the face. In this study, we investigated the craniofacial abnormalities in a mouse model for Keutel syndrome, a rare genetic disease caused by loss-of-function mutations in the matrix Gla Protein (MGP) gene. Keutel syndrome patients show diffuse ectopic calcification of cartilaginous tissues and impaired midface development. Our comparative cephalometric analyses of micro-computed tomography images revealed a severe midface hypoplasia in Mgp−/− mice. In vivo reporter studies demonstrated that the Mgp promoter is highly active at the cranial sutures, cranial base synchondroses, and nasal septum. Interestingly, the cranial sutures of the mutant mice showed normal anatomical features. Although we observed a mild increase in mineralization of the spheno-occipital synchondrosis, it did not reduce the relative length of the cranial base in comparison with total skull length. Contrary to this, we found the nasal septum to be abnormally mineralized and shortened in Mgp−/− mice. Transgenic restoration of Mgp expression in chondrocytes fully corrected the craniofacial anomalies caused by MGP Deficiency, suggesting a local role for MGP in the developing nasal septum. Although there was no up-regulation of markers for hypertrophic chondrocytes, a TUNEL assay showed a marked increase in apoptotic chondrocytes in the calcified nasal septum. Transmission electron microscopy confirmed unusual mineral deposits in the septal extracellular matrix of the mutant mice. Of note, the systemic reduction of the inorganic phosphate level was sufficient to prevent abnormal mineralization of the nasal septum in Mgp−/−;Hyp compound mutants. Our work provides evidence that modulation of local and systemic factors regulating extracellular matrix mineralization can be possible therapeutic strategies to prevent ectopic cartilage calcification and some forms of congenital craniofacial anomalies in humans.
Sapna Syngal - One of the best experts on this subject based on the ideXlab platform.
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microsatellite instability and dna mismatch repair Protein Deficiency in lynch syndrome colorectal polyps
Cancer Prevention Research, 2012Co-Authors: Matthew B Yurgelun, D K Turgeon, Norman E Marcon, Mack T. Ruffin, John A Baron, Sapna Syngal, Robert S. Bresalier, Jason L Hornick, Ajay Goel, Dean E BrennerAbstract:Colorectal cancers associated with Lynch syndrome (LS) are characterized by deficient DNA mismatch repair (MMR) function. Our aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR Protein expression in LS-associated polyps. Sixty two colorectal polyps – 37 adenomas (APs), 23 hyperplastic polyps (HPs), and 2 sessile serrated polyps (SSPs) – from 34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 Proteins by immunohistochemistry (IHC). High-level MSI (MSI-H) was seen in 15/37 (41%) APs, 1/23 (4%) HPs, and 1/2 (50%) SSPs. Loss of MMR Protein expression was seen in 18/36 (50%) APs, 0/21 HPs, and 0/2 SSPs. APs ≥8 mm were significantly more likely to demonstrate MSI-H (OR = 9.98, 95% CI: 1.52-65.65, p = 0.02) and deficient MMR Protein expression (OR = 3.17, 95% CI: 1.20-8.37, p = 0.02) compared with those <8 mm. All (6/6) APs ≥10 mm demonstrated both MSI-H and loss of MMR Protein expression by IHC. Our finding that the prevalence of MMR Deficiency increases with the size of APs suggests that loss of MMR function is a late event in LS-associated colorectal neoplasia. Although testing large APs may be of value in the diagnostic evaluation of patients with suspected LS, the absence of an MMR deficient phenotype in an adenoma cannot be considered strong evidence against LS, as it is with colorectal carcinomas.
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microsatellite instability and dna mismatch repair Protein Deficiency in lynch syndrome colorectal polyps
Cancer Prevention Research, 2012Co-Authors: Matthew B Yurgelun, D K Turgeon, Norman E Marcon, Mack T. Ruffin, John A Baron, Robert S. Bresalier, Jason L Hornick, Ajay Goel, Ananda Sen, Sapna SyngalAbstract:Colorectal cancers associated with Lynch syndrome are characterized by deficient DNA mismatch repair (MMR) function. Our aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR Protein expression in Lynch syndrome-associated polyps. Sixty-two colorectal polyps--37 adenomatous polyps, 23 hyperplastic polyps, and 2 sessile serrated polyps (SSP)--from 34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 Proteins by immunohistochemistry. High-level MSI (MSI-H) was seen in 15 of 37 (41%) adenomatous polyps, one of 23 (4%) hyperplastic polyps, and one of two (50%) SSPs. Loss of MMR Protein expression was seen in 18 of 36 (50%) adenomatous polyps, zero of 21 hyperplastic polyps, and zero of two SSPs. Adenomatous polyps 8 mm or larger in size were significantly more likely to show MSI-H [OR, 9.98; 95% confidence interval (CI), 1.52-65.65; P = 0.02] and deficient MMR Protein expression (OR, 3.17; 95% CI, 1.20-8.37; P = 0.02) compared with those less than 8 mm in size. All (six of six) adenomatous polyps 10 mm or larger in size showed both MSI-H and loss of MMR Protein expression by immunohistochemistry. Our finding that the prevalence of MMR Deficiency increases with the size of adenomatous polyps suggests that loss of MMR function is a late event in Lynch syndrome-associated colorectal neoplasia. Although testing large adenomatous polyps may be of value in the diagnostic evaluation of patients with suspected Lynch syndrome, the absence of an MMR-deficient phenotype in an adenoma cannot be considered as a strong evidence against Lynch syndrome, as it is with colorectal carcinomas.
Matthew B Yurgelun - One of the best experts on this subject based on the ideXlab platform.
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microsatellite instability and dna mismatch repair Protein Deficiency in lynch syndrome colorectal polyps
Cancer Prevention Research, 2012Co-Authors: Matthew B Yurgelun, D K Turgeon, Norman E Marcon, Mack T. Ruffin, John A Baron, Sapna Syngal, Robert S. Bresalier, Jason L Hornick, Ajay Goel, Dean E BrennerAbstract:Colorectal cancers associated with Lynch syndrome (LS) are characterized by deficient DNA mismatch repair (MMR) function. Our aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR Protein expression in LS-associated polyps. Sixty two colorectal polyps – 37 adenomas (APs), 23 hyperplastic polyps (HPs), and 2 sessile serrated polyps (SSPs) – from 34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 Proteins by immunohistochemistry (IHC). High-level MSI (MSI-H) was seen in 15/37 (41%) APs, 1/23 (4%) HPs, and 1/2 (50%) SSPs. Loss of MMR Protein expression was seen in 18/36 (50%) APs, 0/21 HPs, and 0/2 SSPs. APs ≥8 mm were significantly more likely to demonstrate MSI-H (OR = 9.98, 95% CI: 1.52-65.65, p = 0.02) and deficient MMR Protein expression (OR = 3.17, 95% CI: 1.20-8.37, p = 0.02) compared with those <8 mm. All (6/6) APs ≥10 mm demonstrated both MSI-H and loss of MMR Protein expression by IHC. Our finding that the prevalence of MMR Deficiency increases with the size of APs suggests that loss of MMR function is a late event in LS-associated colorectal neoplasia. Although testing large APs may be of value in the diagnostic evaluation of patients with suspected LS, the absence of an MMR deficient phenotype in an adenoma cannot be considered strong evidence against LS, as it is with colorectal carcinomas.
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microsatellite instability and dna mismatch repair Protein Deficiency in lynch syndrome colorectal polyps
Cancer Prevention Research, 2012Co-Authors: Matthew B Yurgelun, D K Turgeon, Norman E Marcon, Mack T. Ruffin, John A Baron, Robert S. Bresalier, Jason L Hornick, Ajay Goel, Ananda Sen, Sapna SyngalAbstract:Colorectal cancers associated with Lynch syndrome are characterized by deficient DNA mismatch repair (MMR) function. Our aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR Protein expression in Lynch syndrome-associated polyps. Sixty-two colorectal polyps--37 adenomatous polyps, 23 hyperplastic polyps, and 2 sessile serrated polyps (SSP)--from 34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 Proteins by immunohistochemistry. High-level MSI (MSI-H) was seen in 15 of 37 (41%) adenomatous polyps, one of 23 (4%) hyperplastic polyps, and one of two (50%) SSPs. Loss of MMR Protein expression was seen in 18 of 36 (50%) adenomatous polyps, zero of 21 hyperplastic polyps, and zero of two SSPs. Adenomatous polyps 8 mm or larger in size were significantly more likely to show MSI-H [OR, 9.98; 95% confidence interval (CI), 1.52-65.65; P = 0.02] and deficient MMR Protein expression (OR, 3.17; 95% CI, 1.20-8.37; P = 0.02) compared with those less than 8 mm in size. All (six of six) adenomatous polyps 10 mm or larger in size showed both MSI-H and loss of MMR Protein expression by immunohistochemistry. Our finding that the prevalence of MMR Deficiency increases with the size of adenomatous polyps suggests that loss of MMR function is a late event in Lynch syndrome-associated colorectal neoplasia. Although testing large adenomatous polyps may be of value in the diagnostic evaluation of patients with suspected Lynch syndrome, the absence of an MMR-deficient phenotype in an adenoma cannot be considered as a strong evidence against Lynch syndrome, as it is with colorectal carcinomas.