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Allen M Spiegel - One of the best experts on this subject based on the ideXlab platform.
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the histopathology of fibrous dysplasia of bone in patients with activating mutations of the gsα gene site specific patterns and recurrent histological hallmarks
The Journal of Pathology, 1999Co-Authors: Mara Riminucci, Andrew Shenker, Allen M Spiegel, Bin Liu, Alessandro Corsi, Pamela Gehron Robey, Paolo BiancoAbstract:Gs alpha mutations and histopathology have been analysed in a series of 13 patients with fibrous dysplasia (FD) of bone, including 12 patients with the McCune-Albright syndrome (MAS) and one patient with monostotic FD. Activating mutations (either R201C or R201H) of the gene encoding the alpha subunit of the stimulatory G protein, Gs, were detected in all cases, including the case of monostotic FD, using a variety of techniques [reverse transcription-polymerase chain reaction (RT-PCR) with Allele-Specific primers, Allele-Specific Oligonucleotide hybridization, and DNA sequencing]. A spectrum of bone lesions associated with such mutations was identified and it was possible to recognize three primary, but distinct, histological patterns, defined here as Chinese writing type, sclerotic/Pagetoid type, and sclerotic/hypercellular type, which are characteristically associated with the axial/appendicular skeleton, cranial bones, or gnathic bones, respectively. Features of FD histopathology were characterized by confocal fluorescence microscopy, which allowed the definition of osteogenic cell shape changes and 'Sharpey fibre bone' as common denominators of all histological subtypes. Defining characteristics of the different subtypes, two of which diverge from standard descriptions of FD and have never been characterized before, were dependent on the amount and structure of bone tissue within the FD lesion. These data emphasize the non-random (site-specific) variability of FD histopathology in patients carrying activating mutations of the Gs alpha gene and provide additional evidence for the occurrence of Gs alpha mutations in cases of FD other than typical MAS.
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the histopathology of fibrous dysplasia of bone in patients with activating mutations of the gsα gene site specific patterns and recurrent histological hallmarks
The Journal of Pathology, 1999Co-Authors: Andrew Shenker, Allen M Spiegel, Mara Riminucci, Bin Liu, Alessandro Corsi, Pamela Gehron Robey, Paolo BiancoAbstract:Gsα mutations and histopathology have been analysed in a series of 13 patients with fibrous dysplasia (FD) of bone, including 12 patients with the McCune–Albright syndrome (MAS) and one patient with monostotic FD. Activating mutations (either R201C or R201H) of the gene encoding the α subunit of the stimulatory G protein, Gs, were detected in all cases, including the case of monostotic FD, using a variety of techniques [reverse transcription-polymerase chain reaction (RT-PCR) with Allele-Specific primers, Allele-Specific Oligonucleotide hybridization, and DNA sequencing]. A spectrum of bone lesions associated with such mutations was identified and it was possible to recognize three primary, but distinct, histological patterns, defined here as Chinese writing type, sclerotic/Pagetoid type, and sclerotic/hypercellular type, which are characteristically associated with the axial/appendicular skeleton, cranial bones, or gnathic bones, respectively. Features of FD histopathology were characterized by confocal fluorescence microscopy, which allowed the definition of osteogenic cell shape changes and ‘Sharpey fibre bone’ as common denominators of all histological subtypes. Defining characteristics of the different subtypes, two of which diverge from standard descriptions of FD and have never been characterized before, were dependent on the amount and structure of bone tissue within the FD lesion. These data emphasize the non-random (site-specific) variability of FD histopathology in patients carrying activating mutations of the Gsα gene and provide additional evidence for the occurrence of Gsα mutations in cases of FD other than typical MAS. Copyright © 1999 John Wiley & Sons, Ltd.
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an activating gs alpha mutation is present in fibrous dysplasia of bone in the mccune albright syndrome
The Journal of Clinical Endocrinology and Metabolism, 1994Co-Authors: Andrew Shenker, Lee S Weinstein, Donald E Sweet, Allen M SpiegelAbstract:McCune-Albright syndrome (MAS) is a sporadic disease characterized by polyostotic fibrous dysplasia, cafe-au-lait spots, and multiple endocrinopathies. The etiology of fibrous dysplasia is unknown. Activating mutations of codon 201 in the gene encoding the alpha-subunit of Gs, the G-protein that stimulates adenylyl cyclase, have been found in all affected MAS tissues that have been studied. Initial attempts to amplify DNA from decalcified paraffin-embedded bone specimens from MAS patients were unsuccessful. Therefore, we analyzed DNA from frozen surgical bone specimens from five MAS patients using polymerase chain reaction and Allele-Specific Oligonucleotide hybridization. Most of the cells in four specimens of dysplastic bone contained a heterozygous mutation encoding substitution of Arg201 of Gs alpha with His, but the mutation was barely detectable in peripheral blood specimens from the patients. Only a small amount of mutant allele was detected in a specimen of normal cortical bone from the fifth pati...
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activating mutations of the stimulatory g protein in the mccune albright syndrome
The New England Journal of Medicine, 1991Co-Authors: Lee S Weinstein, Andrew Shenker, Pablo V Gejman, Maria J Merino, E Friedman, Allen M SpiegelAbstract:Abstract Background. The McCune-Albright syndrome is a sporadic disease characterized by polyostotic fibrous dysplasia, cafe au lait spots, sexual precocity, and hyperfunction of multiple endocrine glands. These manifestations may be explained by a somatic mutation in affected tissues that results in activation of the signal-transduction pathway generating cyclic AMP (cAMP). We analyzed DNA from tissues of patients with the McCune-Albright syndrome for the presence of activating mutations of the gene for the a subunit of the G protein (Gsα) that stimulates cAMP formation. Methods. Genomic DNA fragments encompassing regions (exons 8 and 9) previously found to contain activating missense mutations of the Gsα gene (gsp mutations) in sporadically occurring pituitary tumors were amplified in tissues from four patients with the McCune-Albright syndrome by the polymerase chain reaction. The amplified DNA was analyzed for mutations by denaturing gradient gel electrophoresis and Allele-Specific Oligonucleotide hyb...
Michael Schwarz - One of the best experts on this subject based on the ideXlab platform.
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selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of β catenin mutated mouse liver tumors
Oncogene, 2001Co-Authors: Huriye Aydinlik, Tri Dung Nguyen, Oliver Moennikes, Albrecht Buchmann, Michael SchwarzAbstract:Tumor promoters are non-mutagenic chemicals which increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. Phenobarbital (PB) is an antiepileptic drug which promotes hepatocarcinogenesis in rodents when administered subsequent to an initiating carcinogen like diethylnitrosamine (DEN). Here we have investigated the prevalence and patterns of mutations in two genes, Ha-ras and beta-catenin, both known mutational targets in mouse hepatocarcinogenesis. Liver tumors were generated by a single administration of DEN to 6 week old mice followed by feeding of PB (0.05%) containing or control diet for 39 weeks. Mutations at Ha-ras codon 61 were screened by Allele-Specific Oligonucleotide hybridization; beta-catenin mutations were detected by direct sequencing of PCR products spanning exon 2. In tumors from mice treated with DEN alone, the prevalence of Ha-ras mutations was approximately 30% (6/20), while no beta-catenin mutations (0/13) were detectable in tumors of this treatment group. By contrast, Ha-ras mutations were undetectable in tumors from mice treated with DEN/PB (0/32), while approximately 80% (37/46) of tumors from this group showed beta-catenin mutations. These results demonstrate that PB strongly affects the prevalence of mutations in the two cancer-related genes, presumably by positive and negative selection for cells harboring the respective mutation.
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selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of beta catenin mutated mouse liver tumors
Oncogene, 2001Co-Authors: Huriye Aydinlik, Tri Dung Nguyen, Oliver Moennikes, Albrecht Buchmann, Michael SchwarzAbstract:Tumor promoters are non-mutagenic chemicals which increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. Phenobarbital (PB) is an antiepileptic drug which promotes hepatocarcinogenesis in rodents when administered subsequent to an initiating carcinogen like diethylnitrosamine (DEN). Here we have investigated the prevalence and patterns of mutations in two genes, Ha-ras and beta-catenin, both known mutational targets in mouse hepatocarcinogenesis. Liver tumors were generated by a single administration of DEN to 6 week old mice followed by feeding of PB (0.05%) containing or control diet for 39 weeks. Mutations at Ha-ras codon 61 were screened by Allele-Specific Oligonucleotide hybridization; beta-catenin mutations were detected by direct sequencing of PCR products spanning exon 2. In tumors from mice treated with DEN alone, the prevalence of Ha-ras mutations was approximately 30% (6/20), while no beta-catenin mutations (0/13) were detectable in tumors of this treatment group. By contrast, Ha-ras mutations were undetectable in tumors from mice treated with DEN/PB (0/32), while approximately 80% (37/46) of tumors from this group showed beta-catenin mutations. These results demonstrate that PB strongly affects the prevalence of mutations in the two cancer-related genes, presumably by positive and negative selection for cells harboring the respective mutation.
Francesco Salvatore - One of the best experts on this subject based on the ideXlab platform.
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detection of five rare cystic fibrosis mutations peculiar to southern italy implications in screening for the disease and phenotype characterization for patients with homozygote mutations
Clinical Chemistry, 1999Co-Authors: Giuseppe Castaldo, Antonella Fuccio, Cecile Cazeneuve, Luigi Picci, D Salvatore, Valeria Raia, Maurizio Scarpa, Michel Goossens, Francesco SalvatoreAbstract:Background: The search for the eight most frequent mutations (i.e., ΔF508, G542X, W1282X, N1303K, 1717-1G→A, R553X, 2183AA→G, and I148T) by Allele-Specific Oligonucleotide dot-blot analysis revealed 78% of 396 cystic fibrosis alleles in Southern Italy. The observation of frequent haplotypes on the unidentified cystic fibrosis alleles suggested that a few mutations could account for a large number of unidentified alleles. Methods: We screened most of the coding sequence of the cystic fibrosis transmembrane regulator gene by denaturing gradient gel electrophoresis to determine the spectrum of these mutations in 68 unrelated cystic fibrosis patients bearing one or both unidentified mutations. Results: The screening revealed five mutations, R1158X, 711+1G→T, 4016insT, L1065P, and G1244E, each of which had a frequency of 1.3–1.8% (7% collectively). The 7% increase in the detection rate (85% vs 78%) reduces by >50% the residual risk of being cystic fibrosis carriers for couples who had tested negative by molecular analysis. We therefore designed a second Allele-Specific Oligonucleotide set to analyze the five mutations. Among the patients analyzed, one patient homozygous for the L1065P mutation expressed a mild pulmonary and intestinal form of the disease with pancreatic insufficiency. Two other patients, homozygous for mutations R1158X and 4016insT, both expressed a severe cystic fibrosis phenotype. Conclusions: Five cystic fibrosis mutations are peculiar to patients from Southern Italy. The method described for their analysis is efficient, inexpensive, and can be semi-automated by use of a robotic workstation. The results obtained in patients from Southern Italy may have an impact on laboratories in other countries, given the large migrations of populations from Southern Italy to other countries in the last two centuries.
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novel six nucleotide deletion in the hepatic fructose 1 6 bisphosphate aldolase gene in a patient with hereditary fructose intolerance and enzyme structure function implications
European Journal of Human Genetics, 1999Co-Authors: Rita Santamaria, Luigi Vitagliano, Adriana Zagari, Lucia Zancan, Sonia Tamasi, Paola Izzo, Francesco SalvatoreAbstract:Hereditary fructose intolerance (HFI) is an autosomal recessive human disease that results from the deficiency of the hepatic aldolase isoenzyme. Affected individuals will succumb to the disease unless it is readily diagnosed and fructose eliminated from the diet. Simple and non-invasive diagnosis is now possible by direct DNA analysis that scans for known and unknown mutations. Using a combination of several PCR-based methods (restriction enzyme digestion, allele specific Oligonucleotide hybridisation, single strand conformation analysis and direct sequencing) we identified a novel six-nucleotide deletion in exon 6 of the aldolase B gene (delta 6ex6) that leads to the elimination of two amino acid residues (Leu182 and Val183) leaving the message inframe. The three-dimensional structural alterations induced in the enzyme by delta 6ex6 have been elucidated by molecular graphics analysis using the crystal structure of the rabbit muscle aldolase as reference model. These studies showed that the elimination of Leu182 and Val183 perturbs the correct orientation of adjacent catalytic residues such as Lys146 and Glu187.
Andrew Shenker - One of the best experts on this subject based on the ideXlab platform.
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the histopathology of fibrous dysplasia of bone in patients with activating mutations of the gsα gene site specific patterns and recurrent histological hallmarks
The Journal of Pathology, 1999Co-Authors: Mara Riminucci, Andrew Shenker, Allen M Spiegel, Bin Liu, Alessandro Corsi, Pamela Gehron Robey, Paolo BiancoAbstract:Gs alpha mutations and histopathology have been analysed in a series of 13 patients with fibrous dysplasia (FD) of bone, including 12 patients with the McCune-Albright syndrome (MAS) and one patient with monostotic FD. Activating mutations (either R201C or R201H) of the gene encoding the alpha subunit of the stimulatory G protein, Gs, were detected in all cases, including the case of monostotic FD, using a variety of techniques [reverse transcription-polymerase chain reaction (RT-PCR) with Allele-Specific primers, Allele-Specific Oligonucleotide hybridization, and DNA sequencing]. A spectrum of bone lesions associated with such mutations was identified and it was possible to recognize three primary, but distinct, histological patterns, defined here as Chinese writing type, sclerotic/Pagetoid type, and sclerotic/hypercellular type, which are characteristically associated with the axial/appendicular skeleton, cranial bones, or gnathic bones, respectively. Features of FD histopathology were characterized by confocal fluorescence microscopy, which allowed the definition of osteogenic cell shape changes and 'Sharpey fibre bone' as common denominators of all histological subtypes. Defining characteristics of the different subtypes, two of which diverge from standard descriptions of FD and have never been characterized before, were dependent on the amount and structure of bone tissue within the FD lesion. These data emphasize the non-random (site-specific) variability of FD histopathology in patients carrying activating mutations of the Gs alpha gene and provide additional evidence for the occurrence of Gs alpha mutations in cases of FD other than typical MAS.
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the histopathology of fibrous dysplasia of bone in patients with activating mutations of the gsα gene site specific patterns and recurrent histological hallmarks
The Journal of Pathology, 1999Co-Authors: Andrew Shenker, Allen M Spiegel, Mara Riminucci, Bin Liu, Alessandro Corsi, Pamela Gehron Robey, Paolo BiancoAbstract:Gsα mutations and histopathology have been analysed in a series of 13 patients with fibrous dysplasia (FD) of bone, including 12 patients with the McCune–Albright syndrome (MAS) and one patient with monostotic FD. Activating mutations (either R201C or R201H) of the gene encoding the α subunit of the stimulatory G protein, Gs, were detected in all cases, including the case of monostotic FD, using a variety of techniques [reverse transcription-polymerase chain reaction (RT-PCR) with Allele-Specific primers, Allele-Specific Oligonucleotide hybridization, and DNA sequencing]. A spectrum of bone lesions associated with such mutations was identified and it was possible to recognize three primary, but distinct, histological patterns, defined here as Chinese writing type, sclerotic/Pagetoid type, and sclerotic/hypercellular type, which are characteristically associated with the axial/appendicular skeleton, cranial bones, or gnathic bones, respectively. Features of FD histopathology were characterized by confocal fluorescence microscopy, which allowed the definition of osteogenic cell shape changes and ‘Sharpey fibre bone’ as common denominators of all histological subtypes. Defining characteristics of the different subtypes, two of which diverge from standard descriptions of FD and have never been characterized before, were dependent on the amount and structure of bone tissue within the FD lesion. These data emphasize the non-random (site-specific) variability of FD histopathology in patients carrying activating mutations of the Gsα gene and provide additional evidence for the occurrence of Gsα mutations in cases of FD other than typical MAS. Copyright © 1999 John Wiley & Sons, Ltd.
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an activating gs alpha mutation is present in fibrous dysplasia of bone in the mccune albright syndrome
The Journal of Clinical Endocrinology and Metabolism, 1994Co-Authors: Andrew Shenker, Lee S Weinstein, Donald E Sweet, Allen M SpiegelAbstract:McCune-Albright syndrome (MAS) is a sporadic disease characterized by polyostotic fibrous dysplasia, cafe-au-lait spots, and multiple endocrinopathies. The etiology of fibrous dysplasia is unknown. Activating mutations of codon 201 in the gene encoding the alpha-subunit of Gs, the G-protein that stimulates adenylyl cyclase, have been found in all affected MAS tissues that have been studied. Initial attempts to amplify DNA from decalcified paraffin-embedded bone specimens from MAS patients were unsuccessful. Therefore, we analyzed DNA from frozen surgical bone specimens from five MAS patients using polymerase chain reaction and Allele-Specific Oligonucleotide hybridization. Most of the cells in four specimens of dysplastic bone contained a heterozygous mutation encoding substitution of Arg201 of Gs alpha with His, but the mutation was barely detectable in peripheral blood specimens from the patients. Only a small amount of mutant allele was detected in a specimen of normal cortical bone from the fifth pati...
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activating mutations of the stimulatory g protein in the mccune albright syndrome
The New England Journal of Medicine, 1991Co-Authors: Lee S Weinstein, Andrew Shenker, Pablo V Gejman, Maria J Merino, E Friedman, Allen M SpiegelAbstract:Abstract Background. The McCune-Albright syndrome is a sporadic disease characterized by polyostotic fibrous dysplasia, cafe au lait spots, sexual precocity, and hyperfunction of multiple endocrine glands. These manifestations may be explained by a somatic mutation in affected tissues that results in activation of the signal-transduction pathway generating cyclic AMP (cAMP). We analyzed DNA from tissues of patients with the McCune-Albright syndrome for the presence of activating mutations of the gene for the a subunit of the G protein (Gsα) that stimulates cAMP formation. Methods. Genomic DNA fragments encompassing regions (exons 8 and 9) previously found to contain activating missense mutations of the Gsα gene (gsp mutations) in sporadically occurring pituitary tumors were amplified in tissues from four patients with the McCune-Albright syndrome by the polymerase chain reaction. The amplified DNA was analyzed for mutations by denaturing gradient gel electrophoresis and Allele-Specific Oligonucleotide hyb...
Huriye Aydinlik - One of the best experts on this subject based on the ideXlab platform.
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selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of β catenin mutated mouse liver tumors
Oncogene, 2001Co-Authors: Huriye Aydinlik, Tri Dung Nguyen, Oliver Moennikes, Albrecht Buchmann, Michael SchwarzAbstract:Tumor promoters are non-mutagenic chemicals which increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. Phenobarbital (PB) is an antiepileptic drug which promotes hepatocarcinogenesis in rodents when administered subsequent to an initiating carcinogen like diethylnitrosamine (DEN). Here we have investigated the prevalence and patterns of mutations in two genes, Ha-ras and beta-catenin, both known mutational targets in mouse hepatocarcinogenesis. Liver tumors were generated by a single administration of DEN to 6 week old mice followed by feeding of PB (0.05%) containing or control diet for 39 weeks. Mutations at Ha-ras codon 61 were screened by Allele-Specific Oligonucleotide hybridization; beta-catenin mutations were detected by direct sequencing of PCR products spanning exon 2. In tumors from mice treated with DEN alone, the prevalence of Ha-ras mutations was approximately 30% (6/20), while no beta-catenin mutations (0/13) were detectable in tumors of this treatment group. By contrast, Ha-ras mutations were undetectable in tumors from mice treated with DEN/PB (0/32), while approximately 80% (37/46) of tumors from this group showed beta-catenin mutations. These results demonstrate that PB strongly affects the prevalence of mutations in the two cancer-related genes, presumably by positive and negative selection for cells harboring the respective mutation.
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selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of beta catenin mutated mouse liver tumors
Oncogene, 2001Co-Authors: Huriye Aydinlik, Tri Dung Nguyen, Oliver Moennikes, Albrecht Buchmann, Michael SchwarzAbstract:Tumor promoters are non-mutagenic chemicals which increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. Phenobarbital (PB) is an antiepileptic drug which promotes hepatocarcinogenesis in rodents when administered subsequent to an initiating carcinogen like diethylnitrosamine (DEN). Here we have investigated the prevalence and patterns of mutations in two genes, Ha-ras and beta-catenin, both known mutational targets in mouse hepatocarcinogenesis. Liver tumors were generated by a single administration of DEN to 6 week old mice followed by feeding of PB (0.05%) containing or control diet for 39 weeks. Mutations at Ha-ras codon 61 were screened by Allele-Specific Oligonucleotide hybridization; beta-catenin mutations were detected by direct sequencing of PCR products spanning exon 2. In tumors from mice treated with DEN alone, the prevalence of Ha-ras mutations was approximately 30% (6/20), while no beta-catenin mutations (0/13) were detectable in tumors of this treatment group. By contrast, Ha-ras mutations were undetectable in tumors from mice treated with DEN/PB (0/32), while approximately 80% (37/46) of tumors from this group showed beta-catenin mutations. These results demonstrate that PB strongly affects the prevalence of mutations in the two cancer-related genes, presumably by positive and negative selection for cells harboring the respective mutation.