60 results on '"Patrosso MC"'
Search Results
2. Molecular screening of PDGFRA and PDGFRB genes in KIT and FLT3 negative core binding factor leukemias
- Author
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Cairoli, R, Trojani, A, Ripamonti, CB, Penco, S, Beghini, A, Nadali, GP, Elice, F, Viola, A, Castagnola, C, Colapietro, P, Grillo, G, Pezzetti, P, Ravelli, E, Marocchi, A, Patrosso, MC, Cuneo, A, Ferrara, F, Rodeghiero, F, Lazzarino, M, Pizzolo, G, Morra, E, Cairoli, R, Trojani, A, Ripamonti, C, Penco, S, Beghini, A, Nadali, G, Elice, F, Viola, A, Castagnola, C, Colapietro, P, Grillo, G, Pezzetti, P, Ravelli, E, Marocchi, A, Patrosso, M, Cuneo, A, Ferrara, F, Rodeghiero, F, Lazzarino, M, Pizzolo, G, and Morra, E
- Subjects
Hematology - Published
- 2007
3. Bilateral carcinoma in situ of the testis and cystic fibrosis transmembrane conductance regulator (CFTR) mutation in an azoospermic patient with late-onset 21beta-hydroxylase deficiency
- Author
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Foppiani, L, Baffico, M, Lando, G, Cappi, C, De Cassan, P, Patrosso, Mc, Vitali, A, Penco, S, Giusti, Massimo, and Minuto, Francesco
- Published
- 2004
4. SOD1 GENE MUTATIONS IN AMYOTROPHIC LATERAL SCLEROSIS: A RETROSPECTIVE ITALIAN STUDY
- Author
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Battistini, Stefania, Giannini, Fabio, Greco, Giuseppe, Ferrera, L, Marini, V, Causarano, R, Casula, M, Lando, G, Patrosso, Mc, Caponnetto, C, Origine, P, Marocchi, A, Siciliano, G, Carrera, P, Orru', S, Garre', C, and Penco, S.
- Published
- 2003
5. p.H282N and p.Y191H: 2 novel CYP21A2 mutations in Italian congenital adrenal hyperplasia patients
- Author
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Concolino, Paola, Mello, E, Patrosso, Mc, Penco, S, Zuppi, Cecilia, Capoluongo, Ettore Domenico, Zuppi, Cecilia (ORCID:0000-0003-4710-4934), Capoluongo, Ettore Domenico (ORCID:0000-0001-9872-0572), Concolino, Paola, Mello, E, Patrosso, Mc, Penco, S, Zuppi, Cecilia, Capoluongo, Ettore Domenico, Zuppi, Cecilia (ORCID:0000-0003-4710-4934), and Capoluongo, Ettore Domenico (ORCID:0000-0001-9872-0572)
- Abstract
More than 90\% of all cases of congenital adrenal hyperplasia (CAH) result from steroid 21-hydroxylase gene (CYP21A2) mutations. The CYP21A2 gene is located in the human leukocyte antigen (HLA) class III region on the short arm of chromosome 6p21.3, along with an inactive pseudogene, CYP21A1P, that is 98\% homologous in its coding sequence with CYP21A2. Most CYP21A2 mutations result from intergenic recombinations between CYP21A2 and the closely linked CYP21A1P pseudogene. Rare mutations not generated by gene conversion account for only 5\% to 10\% of 21-hydroxylase deficiency alleles. However, detection of these rare and spontaneous mutations has continued to expand worldwide. We identified 2 novel CYP21A2 missense mutations (p.H282N and p.Y191H) in 2 Italian patients with simple-virilizing and nonclassic CAH forms. Functional analysis of these CYP21A2 mutations was performed. Functional in vitro assay for mutagenized CYP21A2 enzymes was performed in transiently transfected mammalian cells to test the residual enzyme activity and the apparent kinetic values. The residual activities obtained allowed us to classify the p.H282N and p.Y191H variants as simple-virilizing and nonclassic CAH associated mutations, respectively. These results correlate with the rate of severity of the patients' disease. This finding provides a further contribution for assisting in the diagnosis of CAH patients.
- Published
- 2012
6. Molecular analysis of PDGFRA and PDGFRB genes by rapid single-strand conformation polymorphism (SSCP) in patients with core-binding factor leukaemias with KIT or FLT3 mutation
- Author
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Trojani, A, Ripamonti, C, Penco, S, Beghini, A, Nadali, G, Di Bona, E, Viola, A, Castagnola, C, Colapietro, P, Grillo, G, Pezzetti, L, Ravelli, E, Patrosso, M, Marocchi, A, Cuneo, A, Ferrara, F, Lazzarino, M, Pizzolo, G, Cairoli, R, Morra, E, Trojani A, Ripamonti CB, Penco S, Beghini A, Nadali G, Di Bona E, Viola A, Castagnola C, Colapietro P, Grillo G, Pezzetti L, Ravelli E, Patrosso MC, Marocchi A, Cuneo A, Ferrara F, Lazzarino M, Pizzolo G, Cairoli R, Morra E., Trojani, A, Ripamonti, C, Penco, S, Beghini, A, Nadali, G, Di Bona, E, Viola, A, Castagnola, C, Colapietro, P, Grillo, G, Pezzetti, L, Ravelli, E, Patrosso, M, Marocchi, A, Cuneo, A, Ferrara, F, Lazzarino, M, Pizzolo, G, Cairoli, R, Morra, E, Trojani A, Ripamonti CB, Penco S, Beghini A, Nadali G, Di Bona E, Viola A, Castagnola C, Colapietro P, Grillo G, Pezzetti L, Ravelli E, Patrosso MC, Marocchi A, Cuneo A, Ferrara F, Lazzarino M, Pizzolo G, Cairoli R, and Morra E.
- Abstract
Background: Mutations involving KIT and FLT3 genes, encoding tyrosine kinase (TK) membrane receptors, are detected in core-binding factor leukaemia (CBFL) patients. PDFGRA and PDGFRB encode class III TK receptors and are involved both in physiological processes and in the pathogenesis of haematological and solid tumours. The aim of this study was to investigate if PDGFR mutations are involved in CBFL. Patients and Methods: In order to detect PDGFR mutations in CBFL, 35 patients without KIT or FLT3 mutations patients were screened by rapid and sensitive single-strand conformation polymorphism (SSCP) analysis. Sequence analysis was performed in polymerase chain reaction (PCR) products showing altered mobility in SSCP analysis in order to determine the nucleotide changes. Results: Three types of single-nucleotide polymorphism (SNP) were detected in the PDGFRA gene (exon 12, exon 13 and exon 18) while no mutation of PDGFRB was detected in the tested CBFLs. Conclusion: These data showed that no pathogenic mutations in PDGFRA and PDGFRB were detected in the context of CBFL without KIT and FLT3 mutations. Thus, PDGFR genes do not seem to be involved in CBFL and future studies are needed to establish the genetic causes of the disease in these particular patients.
- Published
- 2008
7. X-linked thrombocytopenia and Wiskott Aldrich syndrome are allelic diseases with mutations in the WASP gene
- Author
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Villa, A, Notarangelo, L, Macchi, P, Mantuano, E, Cavagni, G, Brugnoni, D, Strina, D, Patrosso, Mc, Ramenghi, Ugo, Sacco, Mg, and Ugazio, Ag
- Published
- 1995
8. Genomic organization of the human VP16 accessory protein (HCF), a housekeeping gene mapping to Xq28
- Author
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Frattini A, Faranda S, Redolfi E, Zucchi I, Villa A, Patrosso MC, Strina D, Susani L, and Vezzoni P
- Published
- 1994
9. Molecular strategies in genetic diagnosis of transthyretin-related hereditary amyloidosis
- Author
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Ferlini, Alessandra, Fini, S, Salvi, F, Patrosso, Mc, Vezzoni, P, and Forabosco, A.
- Published
- 1992
10. p.H282N and p.Y191H: 2 novel CYP21A2 mutations in Italian congenital adrenal hyperplasia patients
- Author
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Silvana Penco, Cecilia Zuppi, Ettore Capoluongo, Enrica Mello, Maria Cristina Patrosso, Paola Concolino, Concolino, P, Mello, E, Patrosso, Mc, Penco, S, Zuppi, C, and Capoluongo, E
- Subjects
Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Pseudogene ,Blotting, Western ,Mutation, Missense ,21-HYDROXYLASE DEFICIENCY ,Human leukocyte antigen ,Biology ,Transfection ,urologic and male genital diseases ,Endocrinology ,Internal medicine ,Chlorocebus aethiops ,Genetic variation ,medicine ,Animals ,Humans ,Missense mutation ,Congenital adrenal hyperplasia ,Gene conversion ,Allele ,Settore BIO/10 - BIOCHIMICA ,Gene ,Genetics ,Adrenal Hyperplasia, Congenital ,Genetic Variation ,nutritional and metabolic diseases ,DNA ,STEROID 21-HYDROXYLASE ,medicine.disease ,Molecular biology ,female genital diseases and pregnancy complications ,COS Cells ,Mutagenesis, Site-Directed ,Female - Abstract
More than 90% of all cases of congenital adrenal hyperplasia (CAH) result from steroid 21-hydroxylase gene (CYP21A2) mutations. The CYP21A2 gene is located in the human leukocyte antigen (HLA) class III region on the short arm of chromosome 6p21.3, along with an inactive pseudogene, CYP21A1P, that is 98% homologous in its coding sequence with CYP21A2. Most CYP21A2 mutations result from intergenic recombinations between CYP21A2 and the closely linked CYP21A1P pseudogene. Rare mutations not generated by gene conversion account for only 5% to 10% of 21-hydroxylase deficiency alleles. However, detection of these rare and spontaneous mutations has continued to expand worldwide. We identified 2 novel CYP21A2 missense mutations (p.H282N and p.Y191H) in 2 Italian patients with simple-virilizing and nonclassic CAH forms. Functional analysis of these CYP21A2 mutations was performed. Functional in vitro assay for mutagenized CYP21A2 enzymes was performed in transiently transfected mammalian cells to test the residual enzyme activity and the apparent kinetic values. The residual activities obtained allowed us to classify the p.H282N and p.Y191H variants as simple-virilizing and nonclassic CAH associated mutations, respectively. These results correlate with the rate of severity of the patients' disease. This finding provides a further contribution for assisting in the diagnosis of CAH patients.
- Published
- 2012
11. An Italian kindred with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
- Author
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Michele Ragno, Maria Cristina Patrosso, Alessandra Ferlini, Hugues Chabriat, Fabrizio Salvi, Giovanna Sirocchi, Luigi Trojano, Elisabeth Tournier-Lasserve, Antonio Manca, M. G. Fiori, Ragno, M, Tournier Lasserve, E, Fiori, Mg, Manca, A, Patrosso, Mc, Ferlini, A, Sirocchi, G, Trojano, Luigi, Chabriat, H, and Salvi, F.
- Subjects
Adult ,Genetic Markers ,Male ,Pathology ,medicine.medical_specialty ,Genetic Linkage ,Central nervous system disease ,Leukoencephalopathy ,Degenerative disease ,medicine ,Dementia ,Humans ,CADASIL ,Vascular dementia ,business.industry ,Diffuse Cerebral Sclerosis of Schilder ,Cerebral Infarction ,Syndrome ,CADASIL Syndrome ,Pseudobulbar palsy ,Middle Aged ,medicine.disease ,Pedigree ,Radiography ,Cerebrovascular Disorders ,Neurology ,Italy ,Female ,Neurology (clinical) ,business - Abstract
Vascular dementia is usually sporadic and associated with definite risk factors. Several cases also occur in a familial fashion, and may affect middle-aged or even younger subjects. Recently, an autosomal dominant inheritance was demonstrated in two unrelated French families, the members of which were affected by stroke-like episodes culminating in progressive dementia. Genetic linkage analysis assigned the disease locus to chromosome 19q12. We report an additional kindred of Italian origin in which at least 16 subjects presented leukoencephalopathic alterations. Recurrent strokes, psychiatric disturbances, dementia, and in 2 members, tetraplegia and pseudobulbar palsy were the hallmarks of this syndrome. Notably, 5 asymptomatic individuals had neuroradiological signs of leukoencephalopathy. Pathological examination of 1 subject revealed a widespread vasculopathy of the perforating arterioles, characterized by deposition of eosinophilic-congophilic material that did not immunostain with antibodies against prion protein, beta-amyloid, cystatin C, transthyretin, or heat-shock protein 70 and was similar to that described in the French families. Based on the maximum lod score, the most likely location for the disease locus was also mapped to chromosome 19q12, and found to coincide with the CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) locus. The present results confirm the existence of a nosologically distinct, autosomal dominant cerebrovascular disease, presenting with recurrent subcortical ischemic strokes independent of vascular risk factors.
- Published
- 1995
12. Screening of PAX6 gene in Italian congenital aniridia patients revealed four novel mutations.
- Author
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Primignani P, Allegrini D, Manfredini E, Romitti L, Mauri L, Patrosso MC, Veniani E, Franzoni A, Del Longo A, Gesu GP, Piozzi E, Damante G, and Penco S
- Subjects
- Aniridia diagnosis, Cataract diagnosis, Child, Child, Preschool, Female, Glaucoma diagnosis, Humans, Infant, Italy, Male, Multiplex Polymerase Chain Reaction, Nystagmus, Pathologic diagnosis, Sequence Analysis, DNA, Aniridia genetics, Mutation, PAX6 Transcription Factor genetics
- Abstract
Purpose: To uncover underlying mutations in a cohort of Italian patients with aniridia, a rare congenital panocular condition with an incidence ranging from 1:64,000 to 1:100,000. The disease may be found isolated or in association with other syndromes characterized by partial or complete absence of the iris and iris hypoplasia., Methods: We analyzed the PAX6 gene in 11 patients with aniridia fulfilling the following inclusion criteria: partial or complete absence of the iris and age < 18 years at the time of diagnosis. DNA sequence analysis was integrated with Multiple Ligation Probe Assay (MLPA) analysis., Results: We identified seven PAX6 mutations, including four novel ones. The majority of mutations lie in the DNA-binding domain and all produce a truncated protein. All tested patients did not have WT1 gene deletions thus excluding the WAGR syndrome. We present the clinical findings in the four cases harboring novel mutations. We were unable to identify mutations in four cases with complete aniridia thus indicating that other gene/s could be involved in the disease., Conclusions: It is important to establish the molecular diagnosis early to avoid repeated and long-term screening for Wilms tumor. Our work further emphasizes that a wide range of ocular phenotypes are associated with loss of function PAX6 mutations. In addition to the possibility of stochastic variations, other genetic variations could play a role as modifier genes, thus giving rise to the observed different ocular phenotypes.
- Published
- 2016
- Full Text
- View/download PDF
13. Detection of the first OCA6 Italian patient in a large cohort of albino subjects.
- Author
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Veniani E, Mauri L, Manfredini E, Gesu GP, Patrosso MC, Zelante L, D'Agruma L, Del Longo A, Mazza M, Piozzi E, Penco S, and Primignani P
- Subjects
- Albinism, Oculocutaneous diagnosis, Child, DNA Mutational Analysis, Exons, Genetic Association Studies, Genetic Markers, Genetic Predisposition to Disease, Humans, Male, Phenotype, Albinism, Oculocutaneous genetics, Antigens, Neoplasm genetics, Membrane Transport Proteins genetics, Mutation
- Published
- 2016
- Full Text
- View/download PDF
14. SOX2, OTX2 and PAX6 analysis in subjects with anophthalmia and microphthalmia.
- Author
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Mauri L, Franzoni A, Scarcello M, Sala S, Garavelli L, Modugno A, Grammatico P, Patrosso MC, Piozzi E, Del Longo A, Gesu GP, Manfredini E, Primignani P, Damante G, and Penco S
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Italy, Male, Middle Aged, Mutation, PAX6 Transcription Factor, Young Adult, Anophthalmos genetics, Eye Proteins genetics, Homeodomain Proteins genetics, Microphthalmos genetics, Otx Transcription Factors genetics, Paired Box Transcription Factors genetics, Repressor Proteins genetics, SOXB1 Transcription Factors genetics
- Abstract
Anophthalmia (A) and microphthalmia (M) are rare developmental anomalies that have significant effects on visual activity. In fraction of A/M subjects, single genetic defects have been identified as causative. In this study we analysed 65 Italian A/M patients, 21 of whom are syndromic, for mutations in SOX2, OTX2 and PAX6 genes. In syndromic patients the presence of genome imbalances through array CGH was also investigated. No mutations were found for OTX2 and PAX6 genes. Three causative SOX2 mutations were found in subjects with syndromic A. In a subject with syndromic signs and monolateral M, two de novo 6.26 Mb and 1.37 Mb deletions in 4q13.2q13.3 have been identified. A SOX2 missense (p.Ala161Ser) mutation was found in 1 out of 39 a subject with non-syndromic monolateral M. Alanine at position 161 is conserved along phylogeny and the p.Ala161Ser mutation is estimated pathogenic by in silico analysis. However, this mutation was also present in the unaffected patient's daughter., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
15. SLC45A2 mutation frequency in Oculocutaneous Albinism Italian patients doesn't differ from other European studies.
- Author
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Mauri L, Barone L, Al Oum M, Del Longo A, Piozzi E, Manfredini E, Stanzial F, Benedicenti F, Penco S, and Patrosso MC
- Subjects
- Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Italy, Male, Albinism, Oculocutaneous genetics, Antigens, Neoplasm genetics, Membrane Transport Proteins genetics, Mutation
- Abstract
Background: Oculocutaneous Albinism (OCA) is a heterogeneous group of inherited diseases involving hair, skin and eyes. To date, six forms are recognized on the effects of different melanogenesis genes. OCA4 is caused by mutations in SLC45A2 showing a heterogeneous phenotype ranging from white hair, blue irides and nystagmus to brown/black hair, brown irides and no nystagmus. The high clinic variety often leads to misdiagnosis. Our aim is to contribute to OCA4 diagnosis defining SLC45A2 genetic variants in Italian patients with OCA without any TYR, OCA2 and TYRP1 gene defects., Materials and Methods: After the clinical diagnosis of OCA, all patients received genetic counseling and genetic test. Automatic sequencing of TYR, OCA2, and TYRP1 genes was performed on DNA of 117 albino patients. Multiplex Ligation-dependent Probe Amplification (MLPA) was carried out on TYR and OCA2 genes to increase the mutation rate. SLC45A2 gene sequencing was then executed in the patients with a single mutation in one of the TYR, OCA2, TYRP1 genes and in the patients, which resulted negative at the screening of these genes., Results: SLC45A2 gene analysis was performed in 41 patients and gene alterations were found in 5 patients. Four previously reported SLC45A2 mutations were found: p.G100S, p.W202C, p.A511E and c.986delC, and three novel variants were identified: p.M265L, p.H94D, and c.1156+1G>A. All the alterations have been detected in the group of patients without mutations in the other OCA genes., Conclusions: Three new variants were identified in OCA4 gene; the analysis allowed the classification of a patient previously misdiagnosed as OA1 because of skin and hair pigmentation presence. The molecular defects in SLC45A2 gene represent the 3.4% in this cohort of Italian patients, similar to other Caucasian populations; our data differ from those previously published by an Italian researcher group, obtained on a smaller cohort of patients., (© 2013 Elsevier B.V. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
16. Paraoxonase 1 L55M, Q192R and paraoxonase 2 S311C alleles in atherothrombosis.
- Author
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Cozzi L, Campolo J, Parolini M, De Maria R, Patrosso MC, Marocchi A, Parodi O, and Penco S
- Subjects
- Alleles, Cysteine blood, Female, Genetic Predisposition to Disease, Genotype, Glutathione blood, Homocysteine blood, Humans, Hypertension genetics, Ischemic Attack, Transient genetics, Lipid Peroxidation, Lipids blood, Male, Malondialdehyde blood, Middle Aged, Myocardial Infarction genetics, Oxidative Stress, Polymorphism, Single Nucleotide, Risk Factors, Stroke genetics, Aryldialkylphosphatase genetics, Thrombosis genetics
- Abstract
Increased oxidative stress is known to play a role in the pathogenesis of atherosclerosis, and polymorphisms in genes encoding for enzymes involved in modulation of oxidant stress, such as paraoxonases (PONs), provide a potentially powerful approach to study the risk of disease susceptibility. Aim of our study is to investigate the possible association among PONs polymorphisms, clinical and metabolic factors, and atherothrombotic events in an Italian population. We evaluated in 105 subjects, with or without atherosclerotic risk factors, the presence of PON1 L55M, PON1 Q192R, and PON2 S311C genetic variants, as well as lipid profile, the concentration of aminothiols (blood reduced glutathione, plasma total glutathione, homocysteine, cysteine, cysteinyl glycine), and malondialdehyde as markers of lipid peroxidation. Clinical, biochemical, and genetic variables were correlated with a history of atherothrombosis. Previous atherothrombotic events were found in 42 patients (40 %): myocardial infarction in 24, stroke or transient ischemic attack in 18. By multiple logistic regression analysis, hypertension (OR = 5.538; 95 % CI 2.202-13.902, P < 0.001), HDL-cholesterol concentration (OR = 0.947; 95 % CI 0.910-0.985, P = 0.007), and the presence of C allele in PON2 gene (OR = 3.595; 95 % CI 1.247-10.361, P = 0.018) were independently associated with atherothrombotic events. Our study sheds light on the role of PON2 as a possible cofactor in determining the risk of events together with the well-known risk markers HDL-cholesterol and hypertension.
- Published
- 2013
- Full Text
- View/download PDF
17. Clues to detect tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among patients with idiopathic recurrent acute pericarditis: results of a multicentre study.
- Author
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Cantarini L, Lucherini OM, Brucato A, Barone L, Cumetti D, Iacoponi F, Rigante D, Brambilla G, Penco S, Brizi MG, Patrosso MC, Valesini G, Frediani B, Galeazzi M, Cimaz R, Paolazzi G, Vitale A, and Imazio M
- Subjects
- Acute Disease, Adrenal Cortex Hormones therapeutic use, Adult, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Colchicine therapeutic use, DNA Mutational Analysis, Female, Fever, Gene Frequency, Genetic Predisposition to Disease, Hereditary Autoinflammatory Diseases complications, Hereditary Autoinflammatory Diseases drug therapy, Hereditary Autoinflammatory Diseases genetics, Hereditary Autoinflammatory Diseases immunology, Humans, Immunosuppressive Agents therapeutic use, Italy, Male, Middle Aged, Odds Ratio, Pedigree, Pericarditis drug therapy, Pericarditis immunology, Phenotype, Prospective Studies, Recurrence, Risk Assessment, Risk Factors, Hereditary Autoinflammatory Diseases diagnosis, Mutation, Pericarditis genetics, Receptors, Tumor Necrosis Factor, Type I genetics
- Abstract
Background: The potential clinical expression of tumor necrosis factor receptor-associated periodic syndrome (TRAPS), in the form of idiopathic recurrent acute pericarditis (IRAP) has not been explored in the medical literature. The aim of this study was to evaluate the incidence of TRAPS mutations in patients with recurrent pericarditis and identify possible clues to TRAPS diagnosis., Methods: Therefore, 131 consecutive Caucasian IRAP patients were investigated for mutations of the TRAPS gene and prospectively evaluated., Results: Out of 131 patients, 8 (6.1%) carried a mutation in the TNFRSF1A gene. Compared with those without genetic mutations, patients with TRAPS mutations had more frequently a positive family history for pericarditis and periodic fever syndromes (p < 0.001), a higher mean number of recurrences after the first year (p < 0.001), on colchicine treatment (p < 0.001), and a higher need of immunosuppressive therapies (p < 0.001)., Conclusion: TRAPS is a cause of recurrent pericarditis in 6% of unselected cases with recurrent pericarditis. A positive family history for pericarditis or periodic fever syndromes, a poor response to colchicine, recurrences after the first year from the index attack or on colchicine treatment, as well as the need of immunosuppressive agents are clues of the possible presence of TNFRSF1A gene mutations in patients with recurrent pericarditis.
- Published
- 2012
- Full Text
- View/download PDF
18. p.H282N and p.Y191H: 2 novel CYP21A2 mutations in Italian congenital adrenal hyperplasia patients.
- Author
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Concolino P, Mello E, Patrosso MC, Penco S, Zuppi C, and Capoluongo E
- Subjects
- Adrenal Hyperplasia, Congenital genetics, Adult, Animals, Blotting, Western, COS Cells, Chlorocebus aethiops, DNA chemistry, DNA genetics, Female, Genetic Variation, Humans, Male, Mutagenesis, Site-Directed methods, Transfection, Adrenal Hyperplasia, Congenital enzymology, Mutation, Missense, Steroid 21-Hydroxylase genetics
- Abstract
More than 90% of all cases of congenital adrenal hyperplasia (CAH) result from steroid 21-hydroxylase gene (CYP21A2) mutations. The CYP21A2 gene is located in the human leukocyte antigen (HLA) class III region on the short arm of chromosome 6p21.3, along with an inactive pseudogene, CYP21A1P, that is 98% homologous in its coding sequence with CYP21A2. Most CYP21A2 mutations result from intergenic recombinations between CYP21A2 and the closely linked CYP21A1P pseudogene. Rare mutations not generated by gene conversion account for only 5% to 10% of 21-hydroxylase deficiency alleles. However, detection of these rare and spontaneous mutations has continued to expand worldwide. We identified 2 novel CYP21A2 missense mutations (p.H282N and p.Y191H) in 2 Italian patients with simple-virilizing and nonclassic CAH forms. Functional analysis of these CYP21A2 mutations was performed. Functional in vitro assay for mutagenized CYP21A2 enzymes was performed in transiently transfected mammalian cells to test the residual enzyme activity and the apparent kinetic values. The residual activities obtained allowed us to classify the p.H282N and p.Y191H variants as simple-virilizing and nonclassic CAH associated mutations, respectively. These results correlate with the rate of severity of the patients' disease. This finding provides a further contribution for assisting in the diagnosis of CAH patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
19. Phenotypic heterogeneity in a SOD1 G93D Italian ALS family: an example of human model to study a complex disease.
- Author
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Penco S, Lunetta C, Mosca L, Maestri E, Avemaria F, Tarlarini C, Patrosso MC, Marocchi A, and Corbo M
- Subjects
- Adult, Disease Progression, Female, Genetic Testing, Humans, Italy, Male, Middle Aged, Mutation, Pedigree, Polymorphism, Genetic, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis physiopathology, Phenotype, Superoxide Dismutase genetics
- Abstract
We report different clinical expression in seven members of a large family with amyotrophic lateral sclerosis (ALS) and the G93D mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene. The ALS clinical course in the proband showed an unusually fast progression of the disease compared to the paucisymptomatic presentation associated to this mutation in the two previously Italian families described. The remaining mutation carriers did not show the aggressive clinical course displayed by the proband. We selected few genes known to be ALS modifiers searching for genetic variants that could explain the wide phenotypic diversity within the family. Exclusion of causative genes such as TDP43, FUS, PGRN and VAPB was performed too. We believe that this kind of family with contrasting phenotypes of ALS may be considered an excellent human model to study the relationship between a wider genetic profile, including modifier genes, and the clinical expression of the disease. Therefore, the novelty of our approach is also represented by the study of a single family to reproduce a composite structure in which search for possible modifier genes/genetic variants linked to SOD1 mutated.
- Published
- 2011
- Full Text
- View/download PDF
20. Genetic variability of the fructosamine 3-kinase gene in diabetic patients.
- Author
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Mosca L, Penco S, Patrosso MC, Marocchi A, Lapolla A, Sartore G, Chilelli NC, Paleari R, and Mosca A
- Subjects
- Adult, Case-Control Studies, Diabetes Mellitus, Type 1 metabolism, Diabetes Mellitus, Type 2 metabolism, Female, Gene Frequency, Glycated Hemoglobin metabolism, Glycosylation, Haplotypes, Humans, Male, Middle Aged, Diabetes Mellitus, Type 1 enzymology, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 2 enzymology, Diabetes Mellitus, Type 2 genetics, Genetic Variation, Phosphotransferases (Alcohol Group Acceptor) genetics
- Abstract
Background: Nonenzymatic glycation appears to be an important factor in the pathogenesis of diabetic complications. Fructosamine 3-kinase (FN3K), initially identified in erythrocytes, appears to be responsible for the removal of fructosamine from proteins, suggesting a protective role in nonenzymatic glycation. Recently, genetic variants in the FN3K gene have been studied in diabetic patients. The aim of our study was the molecular characterization of the FN3K gene in a representative group of Italian patients with type 1 (T1DM) and 2 (T2DM) diabetes mellitus and in a cohort of healthy controls., Methods: Seventy diabetic subjects (35 type 1 and 35 type 2) with stable glycemic control and 33 healthy control subjects were evaluated using PCR and direct sequencing of the FN3K gene. Denaturing high performance liquid chromatography (DHPLC) was used in controls for screening for the presence of the genetic variants previously found in diabetic patients., Results: Seven different genetic variants were identified, five of them already reported and two new: the p.R187X and p.Y239C mutations identified in two females affected by T2DM. No significant association was found between certain polymorphisms and diabetes conditions. Preliminary haplotype studies are also reported. With respect to genotypes, we noted that some were not present in all the investigated cohort, and some were found related to higher glycated hemoglobin compared to others, although not at a significant level, probably because of the small number of subjects investigated., Conclusions: In conclusion, this study identified two new mutations and additional variants within the FN3K gene. This is the first study on FN3K in Italy. Future work is needed to achieve a better understanding of the FN3K enzyme and its possible clinical utility in the management of diabetic patients.
- Published
- 2011
- Full Text
- View/download PDF
21. Lack of association of PON polymorphisms with sporadic ALS in an Italian population.
- Author
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Ricci C, Battistini S, Cozzi L, Benigni M, Origone P, Verriello L, Lunetta C, Cereda C, Milani P, Greco G, Patrosso MC, Causarano R, Caponnetto C, Giannini F, Corbo M, and Penco S
- Subjects
- Aged, Chi-Square Distribution, DNA Mutational Analysis, Female, Genotype, Humans, Italy epidemiology, Male, Middle Aged, Amyotrophic Lateral Sclerosis genetics, Aryldialkylphosphatase genetics, Polymorphism, Single Nucleotide genetics
- Abstract
Paraoxonase (PON) gene polymorphisms have been associated with susceptibility to sporadic amyotrophic lateral sclerosis (ALS). We have investigated the role of the previously associated single nucleotide polymorphisms rs854560, rs662, and rs6954345 in 350 ALS patients and 376 matched controls from Italy. No significant association was observed at genotype and haplotype level. Our data suggest that PON polymorphisms are not involved in ALS pathogenesis in an Italian population., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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22. Genetic variations within KRIT1/CCM1, MGC4607/CCM2 and PDCD10/CCM3 in a large Italian family harbouring a Krit1/CCM1 mutation.
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Pileggi S, Buscone S, Ricci C, Patrosso MC, Marocchi A, Brunori P, Battistini S, and Penco S
- Subjects
- Exons genetics, Family Health, Female, Haplotypes, Humans, Introns genetics, Italy, KRIT1 Protein, Male, Pedigree, Phenotype, Point Mutation, Apoptosis Regulatory Proteins genetics, Carrier Proteins genetics, Genetic Variation, Hemangioma, Cavernous, Central Nervous System genetics, Membrane Proteins genetics, Microtubule-Associated Proteins genetics, Proto-Oncogene Proteins genetics
- Abstract
Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in seizures, haemorrhage, recurrent headaches and focal neurologic deficit. CCMs can occur as an autosomal dominant trait with incomplete penetrance and a wide phenotypic variability. The genes responsible for this disease are KRIT1/CCM1 on chromosome 7q21.2, MGC4607/CCM2 on chromosome 7p15-p13 and PDCD10/CCM3 on chromosome 3q25.2-q27. Mutations in KRIT1/CCM1 account for more than 40% of CCMs. We previously reported a CCM family harbouring the KRIT1/CCM1 1204delAACAA mutation. In order to search for possible explanation of the clinical variability observed, we looked for genetic variation within exons and exon/intron regions in the three genes KRIT1, MGC4607 and PDCD10 associated to the disease within this large family, 23 subjects have been analysed. Identified genetic variations in the three genes are here presented. We believe that genetic variations could interfere with the proper CCM1/CCM2/CCM3 protein complex thus explaining the observed clinical variability.
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- 2010
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23. Molecular screening test in familial forms of cerebral cavernous malformation: the impact of the Multiplex Ligation-dependent Probe Amplification approach.
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Penco S, Ratti R, Bianchi E, Citterio A, Patrosso MC, Marocchi A, Tassi L, La Camera A, and Collice M
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- Female, Heterozygote, Humans, KRIT1 Protein, Male, Molecular Probes, Mutation, Nucleic Acid Amplification Techniques, Young Adult, Apoptosis Regulatory Proteins genetics, Brain Neoplasms genetics, Carrier Proteins genetics, Hemangioma, Cavernous genetics, Membrane Proteins genetics, Microtubule-Associated Proteins genetics, Proto-Oncogene Proteins genetics
- Abstract
Object The purpose of this study was to underline the effectiveness of molecular analysis in cerebral cavernous angioma, with special attention to the familial forms. Methods Multiplex Ligation-dependent Probe Amplification analysis integrates the consecutive sequence analysis of the 3 genes (Krit1/CCM1, MGC4607/CCM2, and PDCD10/CCM3) known to be responsible for cerebral cavernous malformation lesions. Results The Multiplex Ligation-dependent Probe Amplification analysis revealed a new mutation, a heterozygous exon 9/10 deletion of Krit1, in the proband and in all affected family members. Conclusions The identification of the molecular defect allows physicians to screen family members at risk and to identify affected individuals before the onset of clinical symptoms caused by the presence of lesions.
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- 2009
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24. Familial cerebral cavernous malformation: report of a further Italian family.
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Nannucci S, Pescini F, Poggesi A, Ciolli L, Patrosso MC, Marocchi A, Inzitari D, Penco S, and Pantoni L
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- Adult, Brain physiopathology, Cerebellar Diseases genetics, Cerebellar Diseases pathology, Cerebellar Diseases physiopathology, Chromosomes, Human, Pair 7 genetics, DNA Mutational Analysis, Epilepsy genetics, Epilepsy pathology, Epilepsy physiopathology, Exons genetics, Family Health, Female, Genetic Markers genetics, Hemangioma, Cavernous, Central Nervous System physiopathology, Humans, Intracranial Hemorrhages genetics, Intracranial Hemorrhages pathology, Intracranial Hemorrhages physiopathology, Italy, KRIT1 Protein, Male, Middle Aged, Brain pathology, Genetic Predisposition to Disease genetics, Hemangioma, Cavernous, Central Nervous System genetics, Hemangioma, Cavernous, Central Nervous System pathology, Microtubule-Associated Proteins genetics, Mutation genetics, Proto-Oncogene Proteins genetics
- Abstract
Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, headaches, intracerebral hemorrhages, and focal neurological deficits; they can also be clinically silent and may occur as a sporadic or an autosomal dominant condition. Three genes have been identified as causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3, mapping, respectively, on chromosomes 7q, 7p, and 3q. This is a report on an Italian family affected by CCM due to a KRIT1 gene mutation on exon 13. The mother suffered from a cerebellar hematoma and was severely disabled; one son had suffered from intractable seizures and underwent surgery for removal of a cavernous angioma, while another son was asymptomatic. Brain MRI showed CCMs in all patients. This report underlines that a familial form of CCM could be suspected when a patient presents with multiple CCMs; neurologists and neurosurgeons should be aware that genetic testing for these forms is available.
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- 2009
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25. Gene symbol: TYR. Disease: Albinism, oculocutaneous 1.
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Patrosso MC, Lando G, and Penco S
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- Albinism, Oculocutaneous ethnology, Codon, Consanguinity, Female, Homozygote, Humans, Male, Morocco, Albinism, Oculocutaneous genetics, Amino Acid Substitution, Monophenol Monooxygenase genetics, Mutation, Missense
- Published
- 2008
26. Molecular analysis of PDGFRA and PDGFRB genes by rapid single-strand conformation polymorphism (SSCP) in patients with core-binding factor leukaemias with KIT or FLT3 mutation.
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Trojani A, Ripamonti CB, Penco S, Beghini A, Nadali G, Di Bona E, Viola A, Castagnola C, Colapietro P, Grillo G, Pezzetti L, Ravelli E, Patrosso MC, Marocchi A, Cuneo A, Ferrara F, Lazzarino M, Pizzolo G, Cairoli R, and Morra E
- Subjects
- Acute Disease, Adult, Aged, Core Binding Factors genetics, Female, Humans, Male, Middle Aged, Mutation, Polymorphism, Single-Stranded Conformational, Leukemia, Myeloid genetics, Proto-Oncogene Proteins c-kit genetics, Receptor, Platelet-Derived Growth Factor alpha genetics, Receptor, Platelet-Derived Growth Factor beta genetics, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Background: Mutations involving KIT and FLT3 genes, encoding tyrosine kinase (TK) membrane receptors, are detected in core-binding factor leukaemia (CBFL) patients. PDFGRA and PDGFRB encode class III TK receptors and are involved both in physiological processes and in the pathogenesis of haematological and solid tumours. The aim of this study was to investigate if PDGFR mutations are involved in CBFL., Patients and Methods: In order to detect PDGFR mutations in CBFL, 35 patients without KIT or FLT3 mutations patients were screened by rapid and sensitive single-strand conformation polymorphism (SSCP) analysis. Sequence analysis was performed in polymerase chain reaction (PCR) products showing altered mobility in SSCP analysis in order to determine the nucleotide changes., Results: Three types of single-nucleotide polymorphism (SNP) were detected in the PDGFRA gene (exon 12, exon 13 and exon 18) while no mutation of PDGFRB was detected in the tested CBFLs., Conclusion: These data showed that no pathogenic mutations in PDGFRA and PDGFRB were detected in the context of CBFL without KIT and FLT3 mutations. Thus, PDGFR genes do not seem to be involved in CBFL and future studies are needed to establish the genetic causes of the disease in these particular patients.
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- 2008
27. ZPLD1 gene is disrupted in a patient with balanced translocation that exhibits cerebral cavernous malformations.
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Gianfrancesco F, Esposito T, Penco S, Maglione V, Liquori CL, Patrosso MC, Zuffardi O, Ciccodicola A, Marchuk DA, and Squitieri F
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- Adult, Cell Line, Chromosome Breakage, Databases, Protein, Female, Hemangioma, Cavernous, Central Nervous System metabolism, Hemangioma, Cavernous, Central Nervous System pathology, Humans, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear physiology, Magnetic Resonance Imaging, Phenotype, Primary Ovarian Insufficiency complications, Primary Ovarian Insufficiency genetics, RNA, Messenger metabolism, X Chromosome Inactivation genetics, Chromosomes, Human, Pair 3, Hemangioma, Cavernous, Central Nervous System genetics, Membrane Proteins genetics, Membrane Proteins metabolism, Signal Transduction physiology, Translocation, Genetic
- Abstract
The past few years have seen rapid advances in our understanding of the genetics and molecular biology of cerebral cavernous malformations (CCM) with the identification of the CCM1, CCM2, and CCM3 genes. Recently, we have recruited a patient with an X/3 balanced translocation that exhibits CCM. By fluorescent in situ hybridization analysis, sequence analysis tools and database mining procedures, we refined the critical region to an interval of 200-kb and identified the interrupted ZPLD1 gene. We detected that the mRNA expression level of ZPLD1 gene is consistently decreased 2.5-fold versus control (P=0.0006) with allelic loss of gene expression suggesting that this protein may be part of the complex signaling pathway implicated in CCM formation.
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- 2008
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28. New application of intelligent agents in sporadic amyotrophic lateral sclerosis identifies unexpected specific genetic background.
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Penco S, Buscema M, Patrosso MC, Marocchi A, and Grossi E
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- Adult, Aged, Amyotrophic Lateral Sclerosis physiopathology, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome, Human, Humans, Italy, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Polymorphism, Genetic, Amyotrophic Lateral Sclerosis genetics, Neural Networks, Computer
- Abstract
Background: Few genetic factors predisposing to the sporadic form of amyotrophic lateral sclerosis (ALS) have been identified, but the pathology itself seems to be a true multifactorial disease in which complex interactions between environmental and genetic susceptibility factors take place. The purpose of this study was to approach genetic data with an innovative statistical method such as artificial neural networks to identify a possible genetic background predisposing to the disease. A DNA multiarray panel was applied to genotype more than 60 polymorphisms within 35 genes selected from pathways of lipid and homocysteine metabolism, regulation of blood pressure, coagulation, inflammation, cellular adhesion and matrix integrity, in 54 sporadic ALS patients and 208 controls. Advanced intelligent systems based on novel coupling of artificial neural networks and evolutionary algorithms have been applied. The results obtained have been compared with those derived from the use of standard neural networks and classical statistical analysis, Results: Advanced intelligent systems based on novel coupling of artificial neural networks and evolutionary algorithms have been applied. The results obtained have been compared with those derived from the use of standard neural networks and classical statistical analysis. An unexpected discovery of a strong genetic background in sporadic ALS using a DNA multiarray panel and analytical processing of the data with advanced artificial neural networks was found. The predictive accuracy obtained with Linear Discriminant Analysis and Standard Artificial Neural Networks ranged from 70% to 79% (average 75.31%) and from 69.1 to 86.2% (average 76.6%) respectively. The corresponding value obtained with Advanced Intelligent Systems reached an average of 96.0% (range 94.4 to 97.6%). This latter approach allowed the identification of seven genetic variants essential to differentiate cases from controls: apolipoprotein E arg158cys; hepatic lipase -480 C/T; endothelial nitric oxide synthase 690 C/T and glu298asp; vitamin K-dependent coagulation factor seven arg353glu, glycoprotein Ia/IIa 873 G/A and E-selectin ser128arg., Conclusion: This study provides an alternative and reliable method to approach complex diseases. Indeed, the application of a novel artificial intelligence-based method offers a new insight into genetic markers of sporadic ALS pointing out the existence of a strong genetic background.
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- 2008
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29. Prevention and modulation of aminoglycoside ototoxicity (Review).
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Perletti G, Vral A, Patrosso MC, Marras E, Ceriani I, Willems P, Fasano M, and Magri V
- Abstract
More than 60 years after their isolation and characterization, aminoglycoside (AG) antibiotics remain powerful agents in the treatment of severe gram-negative, enterococcal or mycobacterial infections. However, the clinical use of AGs is hampered by nephrotoxicity and ototoxicity, which often develop as a consequence of prolonged courses of therapy, or of administration of increased doses of these drugs. The discovery of non-ototoxic antibacterial agents, showing a wider spectrum of activity, has gradually decreased the use of AGs as first line antibiotics for many systemic infections. However, AGs are now undergoing an unexpected revival, being increasingly indicated for the treatment of severe emerging infections caused by organisms showing resistance to most first-line agents (e.g., multidrug-resistant tuberculosis, complicated nosocomially-acquired acute urinary tract infections). Increasing adoption of aminoglycosides poses again to scientists and physicians the problem of toxicity directed to the kidneys and to the inner ear. In particular, aminoglycoside-induced deafness can be profound and irreversible, especially in genetically predisposed patients. For this reason, an impressive amount of molecular strategies have been developed in the last decade to counteract the ototoxic effect of aminoglycosides. The present article overviews: i) the molecular mechanisms by which aminoglycosides exert their bactericidal activity, ii) the mechanisms whereby AGs exert their ototoxic activity in genetically-predisposed patients, iii) the drugs and compounds that have so far proven to prevent or modulate AG ototoxicity at the preclinical and/or clinical level, and iv) the dosage regimens that have so far been suggested to decrease the incidence of episodes of AG-induced ototoxicity.
- Published
- 2008
30. Glutamate-cysteine ligase polymorphism, hypertension, and male sex are associated with cardiovascular events. Biochemical and genetic characterization of Italian subpopulation.
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Campolo J, Penco S, Bianchi E, Colombo L, Parolini M, Caruso R, Sedda V, Patrosso MC, Cighetti G, Marocchi A, and Parodi O
- Subjects
- Adult, Female, Genetic Predisposition to Disease, Genotype, Humans, Ischemic Attack, Transient genetics, Italy, Logistic Models, Male, Middle Aged, Myocardial Infarction genetics, Risk Factors, Sex Factors, Stroke genetics, Glutamate-Cysteine Ligase genetics, Hypertension complications, Ischemic Attack, Transient etiology, Myocardial Infarction etiology, Polymorphism, Genetic, Stroke etiology
- Abstract
Background: Glutathione (GSH) is an important intravascular scavenger that protects endothelial cells from atherosclerosis. However, it is still unknown whether cardiovascular (CV) events are associated with metabolic and genetic factors, linked to GSH synthesis in an Italian subpopulation, and if a glutamate-cysteine ligase polymorphism within the catalytic subunit (GCLC) could affect blood and plasma GSH concentrations., Methods: One hundred subjects, with or without CV risk factors, were enrolled to evaluate plasma and erythrocyte redox status (GSH, homocysteine, cysteine, cysteinylglycine), antioxidant vitamins (alpha-tocopherol and ascorbate), malondialdehyde, a lipid peroxidation product, and the presence of the GCLC-129 C/T polymorphism; an experimental hyperhomocysteinemia after methionine-induced stimulation of transsulfuration pathway was performed in 91% of enrolled subjects. Clinical, biochemical, and genetic variables were correlated with the presence of CV events (myocardial infarction, transient ischemic attacks, and stroke)., Results: By multiple logistic regression analysis, male sex (P = .027), hypertension (P = .001), and GCLC C/T genotype (P = .009) were the only variables associated with events. Plasma alpha-tocopherol content decreased postmethionine in the T allele subjects compared with wild type (P for time x group interaction = .001). Plasma-reduced GSH level was higher in C/T than in C/C genotype subjects at both time points (P for group = .03), whereas intracellular GSH concentration did not differ between the 2 genotype groups either at baseline or postmethionine., Conclusions: GCLC T allele, together with hypertension and male sex, is associated with CV events in our study population. Moreover, after stimulation of transsulfuration, intracellular GSH content is preserved in T allele subjects, probably by increases in GSH turnover and export, and consumption of alpha-tocopherol.
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- 2007
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31. Variations in the coding and regulatory sequences of the angiogenin (ANG) gene are not associated to ALS (amyotrophic lateral sclerosis) in the Italian population.
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Corrado L, Battistini S, Penco S, Bergamaschi L, Testa L, Ricci C, Giannini F, Greco G, Patrosso MC, Pileggi S, Causarano R, Mazzini L, Momigliano-Richiardi P, and D'Alfonso S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis epidemiology, DNA Mutational Analysis, Female, Gene Frequency, Humans, Italy epidemiology, Male, Middle Aged, Amyotrophic Lateral Sclerosis genetics, Disease Susceptibility, Genetic Variation, Promoter Regions, Genetic physiology, Ribonuclease, Pancreatic genetics
- Abstract
Potentially causative missense variations in the ANG gene and a positive association with the synonymous rs11701-G substitution was detected mainly in Irish and Scottish ALS patients. We screened 262 Italian SOD1 negative ALS patients (250 sporadic) and 415 matched controls for sequence variations in the coding, 3'/5' UTR and 5' flanking (642 bp) regions of the ANG gene. We identified 53 sequence variations of which 46 new, 20 with a minor allele frequency (MAF) >or=0.01 and only three localised in the coding sequence, namely the missense I46V, identified in one patient and two controls, and the synonymous G86G and T97T corresponding to rs11701 and rs2228653. None of the detected SNPs or of their haplotypic combinations was significantly associated with ALS susceptibility or clinical features. In conclusion, we did not detect the association with rs11701-G or with any other newly detected variation in the ANG regulatory region. Furthermore we did not identify potentially causal mutations in the coding region.
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- 2007
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32. Clinical, magnetic resonance imaging, and genetic study of 5 Italian families with cerebral cavernous malformation.
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Battistini S, Rocchi R, Cerase A, Citterio A, Tassi L, Lando G, Patrosso MC, Galli R, Brunori P, Sgrò DL, Pitillo G, Lo Russo G, Marocchi A, and Penco S
- Subjects
- Adolescent, Adult, Brain pathology, Brain Neoplasms complications, Central Nervous System Diseases etiology, Child, Child, Preschool, DNA Mutational Analysis, Female, Hemangioma, Cavernous, Central Nervous System complications, Heterozygote, Humans, Italy, KRIT1 Protein, Male, Pedigree, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Hemangioma, Cavernous, Central Nervous System diagnosis, Hemangioma, Cavernous, Central Nervous System genetics, Magnetic Resonance Imaging, Microtubule-Associated Proteins genetics, Mutation, Proto-Oncogene Proteins genetics
- Abstract
Background: Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in seizures, hemorrhage, recurrent headaches, and focal neurologic deficits. These CCMs can occur as sporadic or autosomal dominant conditions, although with incomplete penetrance and variable clinical expression. Three CCM loci have been identified, on chromosomes 7q21-22 (CCM1; Online Mendelian Inheritance in Man [OMIM] 116860), 7p13-15 (CCM2; OMIM 603284), and 3q25.2-27 (CCM3; OMIM 603285), and 3 genes have been cloned, KRIT1 on CCM1, MGC4607 on CCM2, and PDCD10 on CCM3. Mutations in KRIT1 account for more than 40% of CCMs., Objective: To describe the results of a comprehensive evaluation of 5 Italian families affected with CCM., Design: Clinical, magnetic resonance imaging, and KRIT1 gene analysis., Setting: University academic teaching hospitals., Patients: Fifteen patients with CCM diagnosed according to defined criteria and 45 at-risk, symptom-free relatives., Results: Three novel and 2 described mutations were found in KRIT1. The families included 33 KRIT1 mutation carriers, 57.6% of whom had no symptoms. Magnetic resonance imaging revealed CCM lesions in 82.3% of symptom-free mutation carriers., Conclusions: The data confirm both incomplete clinical and neuroimaging penetrance in families with the KRIT1 mutation. This consideration is important in genetic counseling. Moreover, the data emphasize both the importance of magnetic resonance imaging in the diagnosis of CCM and the potential for DNA-based diagnosis to identify subjects at risk.
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- 2007
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33. A novel type of familial transthyretin amyloidosis, ATTR Asn124Ser, with co-localization of kappa light chains.
- Author
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Bergström J, Patrosso MC, Colussi G, Salvadore M, Penco S, Lando G, Marocchi A, Ueda A, Nakamura M, and Ando Y
- Subjects
- Aged, Amino Acid Substitution, Amyloid metabolism, Amyloidosis, Familial immunology, Amyloidosis, Familial metabolism, Base Sequence, DNA genetics, Female, Humans, Immunoglobulin kappa-Chains metabolism, Immunohistochemistry, Point Mutation, Prealbumin metabolism, Thyroid Gland immunology, Thyroid Gland metabolism, Amyloidosis, Familial genetics, Prealbumin genetics
- Abstract
A 68-year-old Italian woman who had a clinical history of thyroidectomy in 2002 presented with slowly progressing renal insufficiency and non-nephrotic proteinurea in 2004. A renal biopsy showed the occurrence of amyloid; the thyroid biopsy previously taken also revealed amyloid infiltration. Other amyloid-containing tissues included bone marrow and heart. The plasma cell level in the bone marrow was found to be less than 5% and both serum and urine samples were positive for a monoclonal kappa light chain band. DNA analysis unexpectedly revealed the presence of a novel transthyretin (TTR) mutation, ATTR Asn124Ser. Histologically, amyloid deposits in the thyroid had a homogeneous appearance with moderate Congophilia. In immunohistochemistry, a kappa light chain antiserum showed positive immunoreactivity with amyloid deposits in the thyroid. Furthermore, a TTR antiserum, anti-TTR50-127, also recognized a number of amyloid deposits stained positive with the kappa light chain antiserum. Overall, the kappa light chain antiserum reacted with most of the amyloid deposits in the thyroid, whereas TTR immunoreactivity was scarcer, with a scattered appearance. In contrast, only the anti-TTR50-127 antiserum labeled amyloid in the kidney, albeit not all deposits. In this study, we report a patient having a novel TTR variant, ATTR Asn124Ser, with co-localization of kappa light chains in the amyloid deposits in the thyroid tissue.
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- 2007
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34. Assessment of the role of genetic polymorphism in venous thrombosis through artificial neural networks.
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Penco S, Grossi E, Cheng S, Intraligi M, Maurelli G, Patrosso MC, Marocchi A, and Buscema M
- Subjects
- Adolescent, Adult, Aged, Case-Control Studies, Computer Simulation, Databases, Factual, Female, Genotype, Humans, Male, Middle Aged, Venous Thrombosis epidemiology, Genes genetics, Genetic Predisposition to Disease, Neural Networks, Computer, Polymorphism, Genetic, Venous Thrombosis genetics
- Abstract
Purpose: To assess the role of genetic polymorphisms in venous thrombosis events (VTE) using Artificial Neural Networks (ANNs), a model for solving non-linear problems frequently associated with complex biological systems, due to interactions between biological, genetic and environmental factors., Methods: A database was generated from a case-control study of venous thrombosis, using 238 patients and 211 controls. The database of 64 variables included age, gender and a panel of 62 genetic variants. Three different ANNs were compared, with logistic regression for the accuracy of predicting cases and controls., Results: ANNs yielded a better performance than the logistic regression algorithm. Indeed, through ANNs models, the 62 variables related to genetic variants were first reduced to a set of 9, and then of 3 (MTHFR 677 C/T, FV arg506gln, ICAM1 gly214arg)., Conclusions: The findings of this study illustrate the power of ANN in evaluating multifactorial data, and show that the different sensitivities of the models of elaboration are related to the characteristics of the data. This may contribute to a better understanding of the role played by genetic polymorphisms in VTE, and help to define, if possible, a test panel of genetic variants to estimate an individual's probability of developing the disease.
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- 2005
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35. SOD1 mutations in amyotrophic lateral sclerosis. Results from a multicenter Italian study.
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Battistini S, Giannini F, Greco G, Bibbò G, Ferrera L, Marini V, Causarano R, Casula M, Lando G, Patrosso MC, Caponnetto C, Origone P, Marocchi A, Del Corona A, Siciliano G, Carrera P, Mascia V, Giagheddu M, Carcassi C, Orrù S, Garrè C, and Penco S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis epidemiology, Blotting, Northern methods, Cohort Studies, DNA Mutational Analysis methods, Exons, Female, Genotype, Glycine genetics, Humans, Introns, Italy epidemiology, Male, Middle Aged, Pedigree, Polymorphism, Genetic, RNA, Messenger biosynthesis, Retrospective Studies, Reverse Transcriptase Polymerase Chain Reaction methods, Serine genetics, Statistics, Nonparametric, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis genetics, Family Health, Mutation, Superoxide Dismutase genetics
- Abstract
Amyotrophic Lateral Sclerosis (ALS), the most common form among motoneuron diseases, is characterized by a progressive neurodegenerative process involving motor neurons in the motor cortex, brain stem and spinal cord. Sporadic (SALS) accounts for the majority of patients but in about 10% of ALS cases the disease is inherited (FALS), usually as an autosomal dominant trait. In the present study we show the results of a referred based multicenter study on the distribution of SOD1 gene mutations in the largest cohort of Italian ALS patients described so far. Two hundred and sixty-four patients (39 FALS and 225 SALS) of Italian origin were studied. In 7 out of 39 FALS patients we found the following SOD1 gene mutations: i) a new G12R missense mutation in exon 1, found in a patient with a slowly progressive disease course; ii) the G41S mutation, in four unrelated patients with rapidly progressive course complicated with cognitive decline in two of them; iii) the L114F mutation, in a patient with a slowly progressive phenotype; iv) the D90A mutation, in a heterozygous patient with atypical phenotype. In addition, in one SALS patient a previously reported synonymous variant S59S was identified. In 17 (3 FALS and 14 SALS) out of 264 patients (6.4 %) the polymorphism A-->C at position 34 of intron 3 (IVS3: + 34 A-->C) was found, and in one FALS patient a novel variant IVS3 + 62 T-->C was identified. The frequency of SOD1 gene mutations (17.9 %) in FALS cases was comparable with that found in other surveys with a similar sample size of ALS cases. No SOD1 gene mutations have been identified in SALS cases. Within FALS cases, The most frequent mutation was the G41S identified in four FALS.
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- 2005
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36. Idiopathic recurrent acute pericarditis: familial Mediterranean fever mutations and disease evolution in a large cohort of Caucasian patients.
- Author
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Brucato A, Shinar Y, Brambilla G, Robbiolo L, Ferrioli G, Patrosso MC, Zanni D, Penco S, Boiani E, Ghirardello A, Caforio AL, Bergantin A, Tombini V, Moreo A, Ashtamkar L, Doria A, Shoenfeld Y, and Livneh A
- Subjects
- Arthritis, Rheumatoid diagnosis, Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid immunology, Autoimmune Diseases genetics, Biological Evolution, DNA Mutational Analysis, Familial Mediterranean Fever complications, Familial Mediterranean Fever diagnosis, Familial Mediterranean Fever immunology, Female, Genetic Predisposition to Disease, Genotype, HLA Antigens genetics, Humans, Italy, Male, Pericarditis etiology, Pericarditis immunology, Sjogren's Syndrome diagnosis, Sjogren's Syndrome genetics, Sjogren's Syndrome immunology, Familial Mediterranean Fever genetics, Mutation, Pericarditis genetics
- Abstract
Idiopathic recurrent acute pericarditis (IRAP) is suspected to be an autoimmune phenomenon. We studied 46 consecutive patients. We looked for: 1) the occurrence of new diagnoses of autoimmune diseases during our follow up; 2) HLA typing; and 3) the presence of the most frequent mutations linked to familial Mediterranean fever (FMF gene or MEFV). HLA typing was done in 21 patients at loci B, DRB1, DQA1 and DQB1. MEFV gene was looked in 23 patients using specific primers. During the follow-up we made a new diagnosis of primary Sjögren's syndrome in four patients (8.7%) and of rheumatoid arthritis in one patient (2.2%). HLA B14, DRB1*01 and DQB1*0202 were significantly more prevalent, but we did not find a typical HLA typing. MEFV gene was searched: exon 10 was checked by sequence and the E148Q mutation by restriction site analysis. No mutations were found. In conclusion, the prevalence of definite immunorheumatological diseases and the absence of the mutations linked to FMF reinforce the notion that idiopathic acute recurrent pericarditis is an autoimmune condition.
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- 2005
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37. Bilateral carcinoma in situ of the testis and cystic fibrosis transmembrane conductance regulator (CFTR) mutation in an azoospermic patient with late-onset 21beta-hydroxylase deficiency.
- Author
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Foppiani L, Baffico M, Lando G, Cappi C, De Cassan P, Patrosso MC, Vitali A, Penco S, Giusti M, and Minuto F
- Subjects
- 17-alpha-Hydroxyprogesterone blood, Adrenal Hyperplasia, Congenital complications, Adult, Carcinoma in Situ complications, Carcinoma in Situ radiotherapy, Dehydroepiandrosterone Sulfate blood, Dexamethasone, Follicle Stimulating Hormone blood, Glucocorticoids, Humans, Male, Mutation, Obesity complications, Steroid 21-Hydroxylase genetics, Testicular Neoplasms complications, Testicular Neoplasms radiotherapy, Testosterone blood, Vas Deferens pathology, Adrenal Hyperplasia, Congenital diagnosis, Carcinoma in Situ diagnosis, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Oligospermia complications, Testicular Neoplasms diagnosis
- Abstract
Testicular cancer can impair spermatogenesis. In addition, chemotherapy or radiotherapy used for its treatment further damage testicular function mainly affecting highly proliferating germ cells. The multifaceted etiology of male infertility includes, among others, alterations of male reproductive tract differentiation such as monolateral or bilateral congenital absence of vas deferens and perturbations in adrenal steroid synthesis on a genetic basis such as 21beta-hydroxylase deficiency. Herein, we report the case of a male patient with primary infertility, probably related to a combination of genetic and acquired factors with different expressions over time.
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- 2004
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38. Effect of incremental doses of folate on homocysteine and metabolically related vitamin concentrations in nondiabetic patients on peritoneal dialysis.
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de Vecchi AF, Novembrino C, Patrosso MC, Cresseri D, Ippolito S, Rosina M, Colucci P, Lando G, and Bamonti Catena F
- Subjects
- Administration, Oral, Aged, Female, Folic Acid blood, Hematinics blood, Humans, Hyperhomocysteinemia blood, Hyperhomocysteinemia genetics, Kidney Failure, Chronic therapy, Male, Methylenetetrahydrofolate Reductase (NADPH2) genetics, Middle Aged, Folic Acid administration & dosage, Hematinics administration & dosage, Homocysteine blood, Hyperhomocysteinemia drug therapy, Kidney Failure, Chronic blood, Peritoneal Dialysis
- Abstract
The role of folate supplementation in reducing hyperhomocystinemia in patients on dialysis has been reported, but the optimal dose of folate is still unknown. The aim of the present study was to investigate whether greater than 5 mg/day folate supplementation provides any additional effect on plasma homocysteine (HCY) levels. The study was prospective, open, and had no control group. Of the 64 eligible nondiabetic patients on peritoneal dialysis with hyperhomocystinemia (>20 micromol/L), 56 were given oral folate (5 mg/day) for 3 months. When Hcy did not fall below 20 micromol/L, folate doses were increased by 5 mg every 3 months to up to 15 mg/day. With 5 mg/day supplementation, serum folate concentrations increased above the upper confidence limit in 23 patients and erythrocyte folate concentrations in 27 patients. Hcy levels decreased to less than 15 micromol/L in 6 cases and by more than 50% in 12 cases. Nineteen of the remaining patients were given 10 mg/day folate. After increasing the dose, serum and erythrocyte folate levels rose above the upper detection limit. In one patient, plasma Hcy concentrations decreased to less than 15 micromol/L. Ten patients were given 15 mg/day oral folate for an additional 3 months with no effect on homocystinemia. This study confirms that oral folate supplementation may improve hyperhomocystinemia even in patients on dialysis with normal serum or erythrocyte folate concentrations. In fact, serum and erythrocyte levels cannot predict the effect of supplementation on plasma Hcy levels. However, 5 mg/day folate supplementation normalized Hcy in 10% of cases and reduced Hcy levels in another 21%. Increasing the folate dose to greater than 5 mg/day had a minimal (10 mg/day) or no (15 mg/day) additional effect on Hcy concentrations. Despite the minimal effect of increasing folate doses, given the low cost, the absence of side effects, and the high cardiovascular risk for patients on peritoneal dialysis, a careful attempt to increase the dose of oral folate up to 10 mg/day might be suggested.
- Published
- 2003
- Full Text
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39. Frequency of butyrylcholinesterase gene mutations in individuals with abnormal inhibition numbers: an Italian-population study.
- Author
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Lando G, Mosca A, Bonora R, Azzario F, Penco S, Marocchi A, Panteghini M, and Patrosso MC
- Subjects
- Amino Acid Substitution, Base Sequence, Cholinesterase Inhibitors pharmacology, DNA Primers, Genetics, Behavioral, Genotype, Humans, Italy, Butyrylcholinesterase genetics, Dibucaine pharmacology, Fluorides pharmacology, Gene Frequency, Genetic Variation genetics, Inhibition, Psychological, Mutation, Missense
- Abstract
Objectives: More than 30 genetic variants of serum cholinesterase (butyrylcholinesterase, BChE) have been described. Some of them (the atypical and the fluoride-resistant variants) are well known because carriers are prone to develop prolonged apnea following the administration of the muscle relaxant succinylcholine. Genotype characterization is therefore important in order to prevent such episodes. Genetic studies have so far focused on selected individuals or families rather than on the random population., Methods: From a large group of healthy blood donors (n = 2609), we selected all the 58 individuals with low serum cholinesterase activity: among them 28 subjects had abnormal dibucaine and fluoride inhibition numbers. Twenty-five mutations in the coding region of the human cholinesterase gene were analyzed., Results: All individuals with abnormal inhibition numbers were homozygotes or double heterozygotes in several mutations. Asp70Gly (Atypical variant) and Ala539Thr (K variant) were the most frequently observed amino acid substitutions. The majority of subjects with low BChE activity but normal dibucaine and fluoride number presented only the K form. We analyzed 106 randomly chosen subjects for K and atypical variants. Carriers of these alleles were at risk of low BChE activity (OR = 9.55, 95%CI, 5.61-16.26 and OR = 30.33, 95%CI, 7.05-130.52 respectively)., Conclusions: Data obtained from this study help to better define the etiology of low BChE activity and the role of the rather common K allele. It is the first time that such a large population has been screened for so many mutations. BChE is also implicated in detoxifying cocaine; therefore genetic analysis could be useful in cases of cocaine toxicity in Italian subjects.
- Published
- 2003
- Full Text
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40. Assay using succinyldithiocholine as substrate: the method of choice for the measurement of cholinesterase catalytic activity in serum to diagnose succinyldicholine sensitivity.
- Author
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Mosca A, Bonora R, Ceriotti F, Franzini C, Lando G, Patrosso MC, Zaninotto M, and Panteghini M
- Subjects
- Anesthetics, Local pharmacology, Butyrylthiocholine metabolism, Cariostatic Agents pharmacology, Catalysis, Cholinesterase Inhibitors pharmacology, Cholinesterases genetics, DNA blood, DNA Mutational Analysis, Dibucaine pharmacology, Fluorides pharmacology, Genotype, Heterozygote, Homozygote, Humans, ROC Curve, Sensitivity and Specificity, Substrate Specificity, Thiocholine metabolism, Apnea enzymology, Cholinesterases blood, Succinylcholine analogs & derivatives, Succinylcholine metabolism, Thiocholine analogs & derivatives
- Abstract
No comparative information is available concerning the ability of various cholinesterase (ChE) methods to identify succinyldicholine-sensitive patients, purely on the basis of the enzyme activity recorded in serum. Here, we evaluated six different methods for the measurement of ChE activity; 131 subjects were subdivided according to ChE phenotype and, therefore, to succinyldicholine sensitivity. ChE phenotype was determined by measuring dibucaine and fluoride numbers. DNA analysis was also performed to confirm correlation between the phenotype classification used in the study and the ChE genotype. The tested methods were significantly different in their ability to discriminate between the subjects with and without succinyldicholine-sensitive phenotypes. The succinyldithiocholine/5,5'-dithio-bis(2-nitrobenzoate) (DTNB) method showed the highest accuracy (area under the receiver operating characteristic (ROC) curve 0.97) followed by the propionylthiocholine/DTNB method (area under the ROC curve 0.94). On the other hand, the two methods using butyrylthiocholine as substrate and that employing benzoylcholine showed limited clinical utility in discriminating subjects at risk of prolonged apnea (area under the ROC curve < or = 0.9). Using the succinyldithiocholine method, a value < or = 23 U/l was approximately five times as likely to occur in a sensitive individual as in a normal one.
- Published
- 2003
- Full Text
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41. Novel transthyretin missense mutation (Thr34) in an Italian family with hereditary amyloidosis.
- Author
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Patrosso MC, Salvi F, De Grandis D, Vezzoni P, Jacobson DR, and Ferlini A
- Subjects
- Aged, DNA Mutational Analysis, Female, Humans, Italy, Male, Middle Aged, Pedigree, Polymerase Chain Reaction methods, Threonine genetics, Amyloidosis genetics, Point Mutation genetics, Prealbumin genetics
- Abstract
We report on the genetic and molecular characterisation of an Italian family with a late-onset, autosomal dominant transthyretin amyloidosis. The transthyretin gene was analysed by polymerase chain reaction (PCR), restriction generating PCR, and sequencing, allowing us to discover in one allele a novel point mutation. It consists of a G to C transversion at position 1692 of the genomic sequence, leading to a Thr for Arg substitution at the position 34 of the polypeptidic chain. This mutation is associated with a severe sensory-motor peripheral neuropathy and a restrictive cardiomyopathy.
- Published
- 1998
- Full Text
- View/download PDF
42. Electromyographic findings in transthyretin (TTR)-related familial amyloid polyneuropathy (FAP).
- Author
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Montagna P, Marchello L, Plasmati R, Ferlini A, Patrosso MC, and Salvi F
- Subjects
- Adult, Electromyography, Female, Humans, Liver Transplantation, Male, Amyloid Neuropathies physiopathology, Prealbumin metabolism, Skin physiopathology, Sural Nerve physiopathology
- Abstract
Affected members and asymptomatic relatives of 9 Italian families with transthyretin (TTR)-related hereditary amyloidosis carrying different TTR mutations (Met30, Pro36, Ala47, Ala49, Gln89) were followed up with repeated EMG investigations. In 3 patients, spontaneous myoclonic discharges with synkinesia were found in the facial muscles. EMG signs of chronic denervation with features of proximal neural involvement were also found in proximal limb muscles. Neuropathy worsened step-wise with progressing clinical stage. Sympathetic skin responses progressively decreased, disappearing in the late stages of the disease. Symptomatic relatives carrying the TTR mutations had significantly reduced sensory conduction velocities and amplitudes of compound motor action potentials. Follow-up studies in 3 patients after liver transplant showed progression of sensory-motor neuropathy 1 year after the transplant, and a slight improvement 18 months later. Based on our electrophysiological findings and a review of the literature, we propose that TTR-related FAP type I be considered not only a peripheral neuropathy, but also a meningoradiculopathy due to deposition of amyloidogenic TTR in the leptomeninges.
- Published
- 1996
43. Electrophoretic separation of biopolymers in a matrix of polyacrylamide covalently linked to agarose.
- Author
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Chiari M, Campoleoni A, Conti P, Felli C, Patrosso MC, and Brogren CH
- Subjects
- Biopolymers, Carbohydrate Sequence, Electrophoresis, Agar Gel methods, Electrophoresis, Polyacrylamide Gel methods, Molecular Sequence Data, Molecular Structure, Sepharose, DNA analysis, Electrophoresis methods, Proteins analysis
- Abstract
A new type of agarose polyacrylamide mixed-bed gel, obtained by simultaneous gelation of a novel type of allyl-activated agarose and its copolymerization with acrylamide, has pore sizes intermediate between those of polyacrylamide and agarose. The process used to activate the agarose chains enables the substitution to be controlled. As indicated by nuclear magnetic resonance (NMR), only one allyl group was inserted per agarose basic unit. Several formulations of mixed-bed gels, containing different percentages of acrylamide, were compared with conventional polyacrylamide or agarose gels. Resolution, migration distance and band sharpness of different molecular mass fragments were evaluated, with two types of gel run side-by-side in a vertical or horizontal system. The faster electrophoretic mobility of DNA in dilute mix-bed gels and the improved separation of the component of high molecular mass (1 to 6 kbp) of the 1 kbp ladder indicate that these matrices have larger porosity than any dilute polyacrylamide formulations. Sodium dodecyl sulfate (SDS)-protein complexes migrate in the mixed gels faster than in polyacrylamide gels of the same %T.
- Published
- 1996
- Full Text
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44. X-linked bulbar and spinal muscular atrophy, or Kennedy disease: clinical, neurophysiological, neuropathological, neuropsychological and molecular study of a large family.
- Author
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Guidetti D, Vescovini E, Motti L, Ghidoni E, Gemignani F, Marbini A, Patrosso MC, Ferlini A, and Solime F
- Subjects
- Adolescent, Adult, Aged, Child, Female, Follow-Up Studies, Humans, Male, Middle Aged, Motor Neuron Disease pathology, Muscular Atrophy pathology, Pedigree, Receptors, Androgen genetics, Genetic Linkage, Motor Neuron Disease genetics, Muscular Atrophy genetics, X Chromosome
- Abstract
We report the clinical, neurophysiological, neuropsychological, neuropathological and molecular findings in a large family with X-linked bulbar and spinal muscular atrophy (X-BSMA). Molecular study, performed in 28 family members, showed an increase in the number of CAG repeats in 6 affected males (including 2 presymptomatic patients), and in 10 females, of whom 5 were obligate carriers. All symptomatic patients showed, besides the typical manifestation of X-BSMA, neurophysiological signs of sensory nerve involvement, and abnormal findings in neuropsychological tests. Sural nerve biopsy, performed in two patients, was consistent with axonal atrophy and slow-rate degeneration, with secondary demyelination. Neurophysiological alterations were also present in 6 out of 8 carriers, consisting of neurogenic EMG changes in 3 cases and abnormal sensory action potentials (SAP) and reduced conduction velocity of the sural nerve in 3 cases. Abnormalities of at last two neuropsychological tests were found in 6 out of 8 carriers. Alterations of the sensory nerves in X-BSMA patients have been previously reported in some cases; however, we demonstrate for the first time sensory nerve involvement also in carriers. Evidence of central nervous system involvement, with neuropsychological impairment in all symptomatic patients and in some carriers, is another feature of this family, not previously reported in X-BSMA. In spite of the variable phenotypic features, the number of CAG repeats ranged from 40 to 44 in the affected patients, indicating that phenotypic expression was not related to the size of the mutation, but was probably age-related.
- Published
- 1996
- Full Text
- View/download PDF
45. Homozygosity and heterozygosity for the transthyretin Leu64 mutation: clinical, biochemical and molecular findings.
- Author
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Ferlini A, Salvi F, Uncini A, el-Chami J, Winter P, Altland K, Repetto M, Littardi M, Campoleoni A, Vezzoni P, and Patrosso MC
- Subjects
- Aged, Base Sequence, Female, Heterozygote, Homozygote, Humans, Male, Middle Aged, Molecular Sequence Data, Oligodeoxyribonucleotides, Pedigree, Amyloidosis genetics, Leucine, Point Mutation, Prealbumin genetics
- Abstract
Transthyretin gene point mutations cause hereditary amyloidosis with an autosomal dominant pattern of inheritance. The disease usually manifests itself in heterozygous patients, although a few homozygotes have been reported. We describe two unrelated patients carrying the Leu64 mutation, one of whom presents a homozygous genotype (Family B). Homozygosity was confirmed by sequence analysis, RG-PCR and double one-dimensional electrophoresis of the plasma protein. Although the clinical picture of the homozygous patient of Family B was more severe than that shown by the heterozygous members of Family A, the variability often displayed by FAP patients does not allow any firm conclusion about the role of homozygosity in the seriousness of the disease.
- Published
- 1996
- Full Text
- View/download PDF
46. An Italian kindred with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
- Author
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Ragno M, Tournier-Lasserve E, Fiori MG, Manca A, Patrosso MC, Ferlini A, Sirocchi G, Trojano L, Chabriat H, and Salvi F
- Subjects
- Adult, Cerebral Infarction diagnostic imaging, Cerebral Infarction genetics, Cerebral Infarction pathology, Cerebrovascular Disorders diagnostic imaging, Cerebrovascular Disorders pathology, Diffuse Cerebral Sclerosis of Schilder diagnostic imaging, Diffuse Cerebral Sclerosis of Schilder pathology, Female, Genetic Linkage, Genetic Markers, Humans, Italy, Male, Middle Aged, Pedigree, Radiography, Syndrome, Cerebrovascular Disorders genetics, Diffuse Cerebral Sclerosis of Schilder genetics
- Abstract
Vascular dementia is usually sporadic and associated with definite risk factors. Several cases also occur in a familial fashion, and may affect middle-aged or even younger subjects. Recently, an autosomal dominant inheritance was demonstrated in two unrelated French families, the members of which were affected by stroke-like episodes culminating in progressive dementia. Genetic linkage analysis assigned the disease locus to chromosome 19q12. We report an additional kindred of Italian origin in which at least 16 subjects presented leukoencephalopathic alterations. Recurrent strokes, psychiatric disturbances, dementia, and in 2 members, tetraplegia and pseudobulbar palsy were the hallmarks of this syndrome. Notably, 5 asymptomatic individuals had neuroradiological signs of leukoencephalopathy. Pathological examination of 1 subject revealed a widespread vasculopathy of the perforating arterioles, characterized by deposition of eosinophilic-congophilic material that did not immunostain with antibodies against prion protein, beta-amyloid, cystatin C, transthyretin, or heat-shock protein 70 and was similar to that described in the French families. Based on the maximum lod score, the most likely location for the disease locus was also mapped to chromosome 19q12, and found to coincide with the CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) locus. The present results confirm the existence of a nosologically distinct, autosomal dominant cerebrovascular disease, presenting with recurrent subcortical ischemic strokes independent of vascular risk factors.
- Published
- 1995
- Full Text
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47. X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene.
- Author
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Villa A, Notarangelo L, Macchi P, Mantuano E, Cavagni G, Brugnoni D, Strina D, Patrosso MC, Ramenghi U, and Sacco MG
- Subjects
- Base Sequence, Child, DNA genetics, DNA Primers genetics, Exons, Frameshift Mutation, Genes, Humans, Introns, Male, Molecular Sequence Data, Point Mutation, Polymerase Chain Reaction, Wiskott-Aldrich Syndrome Protein, Alleles, Mutation, Proteins genetics, Thrombocytopenia genetics, Wiskott-Aldrich Syndrome genetics, X Chromosome
- Abstract
X-linked thrombocytopenia (XLT) is a rare recessive hereditary disorder characterized by isolated thrombocytopenia with small-sized platelets. The XLT locus has been located to chromosome Xp11 by linkage analysis, which is also where the recently cloned Wiskott-Aldrich syndrome (WAS) gene, maps. The relationship between XLT and WAS has long been debated; they might be due to different mutations of the same gene or to mutations in different genes. We now show that mutations in the WAS gene, different from those found in WAS patients, are present in three unrelated male patients with isolated thrombocytopenia and small-sized platelets. Our results demonstrate that XLT and WAS are allelic forms of the same disease, but the causes of the differences need to be further investigated.
- Published
- 1995
- Full Text
- View/download PDF
48. Androgen receptor gene (CAG)n repeat analysis in the differential diagnosis between Kennedy disease and other motoneuron disorders.
- Author
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Ferlini A, Patrosso MC, Guidetti D, Merlini L, Uncini A, Ragno M, Plasmati R, Fini S, Repetto M, and Vezzoni P
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Diagnosis, Differential, Female, Genetic Linkage, Gynecomastia genetics, Humans, Male, Middle Aged, Molecular Sequence Data, Pedigree, X Chromosome genetics, Motor Neuron Disease diagnosis, Motor Neuron Disease genetics, Muscular Atrophy, Spinal diagnosis, Muscular Atrophy, Spinal genetics, Receptors, Androgen genetics, Repetitive Sequences, Nucleic Acid
- Abstract
An increase in the number of (CAG)n repeats in the first coding exon of the androgen receptor (AR) gene has been strongly associated with Kennedy disease (KD) (spinal and bulbar muscular atrophy). This is an X-linked hereditary disorder characterized by motoneuron degeneration occurring in adults together with gynecomastia and hyperestrogenemia. We have performed AR gene molecular analysis in several members of a large family with KD as well as in 25 sporadic patients suffering from heterogeneous motoneuron disease (MND). An increase in the length of the (CAG)n repeats was detected, as expected, in all the affected males and in obligatory carrier females, some of which had minor signs of lower motoneuron involvement. There was only one possible exception, one young male with initial signs of the disease, who had an apparent normal length allele. An increased pathological allele was also found in 3 patients with MND. This indicates that the analysis of (CAG)n repeats of the AR gene plays a role in the differential diagnosis of this heterogeneous group of neurological diseases.
- Published
- 1995
- Full Text
- View/download PDF
49. Genomic organization of the human VP16 accessory protein, a housekeeping gene (HCFC1) mapping to Xq28.
- Author
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Frattini A, Faranda S, Redolfi E, Zucchi I, Villa A, Patrosso MC, Strina D, Susani L, and Vezzoni P
- Subjects
- Base Sequence, Chromosome Mapping, Chromosomes, Artificial, Yeast, Host Cell Factor C1, Humans, Molecular Sequence Data, Protein Biosynthesis, RNA Splicing, RNA, Messenger genetics, Proteins genetics, Transcription Factors, X Chromosome
- Abstract
The region between DXS52 and Factor VIII gene in the human Xq28 chromosomal band contains a G+C-rich isochore to which many genes have been mapped. We report here the isolation and characterization of a transcript mapping about 50 kb telomeric from the vasopressin type 2 receptor gene in a 180-kb YACs/cosmid contig containing the L1CAM gene at its centromeric end. The determined transcribed sequence from a human fetal brain library is identical to that of the recently identified accessory protein HCFC1 (host cell factor, also called C1) that activates herpes simplex virus VP16 (alpha TIF) transactivator protein for association with the octamer motif-binding protein Oct-1 (Cell 74: 115, 1993). The gene is expressed in a ubiquitous pattern and a larger transcript of approximately 10 kb is present in all the tissues tested, while an alternatively spliced RNA of approximately 8.0 kb is present in muscle and heart tissues. Genomic sequencing allowed us to determine that the sequenced transcript is assembled from 26 exons spread over a relatively small genomic region of approximately 24 kb. This alllowed us to determine that a previously reported cDNA clone arises from the splicing out of an internal portion of exon 8 which does not change the reading frame. All together these results raise the possibility that alternative mRNA processing could partly contribute to the diversity of the polypeptide HCFC1 family in a subset of tissues.
- Published
- 1994
- Full Text
- View/download PDF
50. The exon-intron organization of the human X-linked gene (FLN1) encoding actin-binding protein 280.
- Author
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Patrosso MC, Repetto M, Villa A, Milanesi L, Frattini A, Faranda S, Mancini M, Maestrini E, Toniolo D, and Vezzoni P
- Subjects
- Amino Acid Sequence, Base Sequence, Contractile Proteins chemistry, Exons, Filamins, Genes, Humans, Introns, Microfilament Proteins chemistry, Molecular Sequence Data, Protein Structure, Tertiary, RNA Splicing, Repetitive Sequences, Nucleic Acid, Contractile Proteins genetics, Microfilament Proteins genetics, X Chromosome
- Abstract
We have determined the exon-intron organization of the human X-linked gene (FLN1) encoding actin-binding protein 280 (filamin), a ubiquitous protein that plays an important role in the mechanochemical activities of cells through its association with actin filaments and membrane components. The gene is composed of 47 exons spanning approximately 26 kb. The first and part of the second exon are untranslated. The actin-binding domain at the N-terminus is encoded by exons 2 to 5. The 96-amino-acid repeats corresponding to the elongated rod backbone of the protein are encoded by the remaining 42 exons: size, location, and boundaries of the exons cannot be easily correlated with the repeated structure, while sequences interrupting the repeats (the two hinge segments preceding repeats 16 and 24 and the 8-amino-acid (aa) segment interrupting the 15th repeat) were encoded by separate exons, suggesting that they may be recent additions to the X-linked protein. The 8-aa segment is encoded by exon 29, which is alternatively spliced.
- Published
- 1994
- Full Text
- View/download PDF
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