- EDUCATION AND TRAINING 1980: MD, School of Medicine, University of Rome, La Sapienza, Italy, summa cum lau... moreEDUCATION AND TRAINING
1980: MD, School of Medicine, University of Rome, La Sapienza, Italy, summa cum laude
1980-1983: Postdoctoral fellow, Laboratory of Virology, Istituto Superiore di Sanita, Rome Italy
1983-1984: Postdoctoral fellow, Laboratory of Cellular and Molecular Biology, National Cancer Inst., NIH, Bethesda, MD and Frederick Cancer Research Facility, Frederick, MD
1985-1987: Research Associate, Laboratory of Viral Oncology, Memorial Sloan-Kettering Cancer Center, New York, N.Y.
EMPLOYMENT AND RESEARCH EXPERIENCE
1988-1993: Staff Scientist, European Molecular Biology Laboratory, Heidelberg, Germany
1993-2000: Associate Professor of Histology, School of Medicine, University of Siena.
2000-date: Professor of Histology, School of Medicine, University of Siena.
1993-2002: Director, Growth Factors Unit, DIBIT, H S Raffaele, Milano
1994-2000: Director PhD International PhD Programme, H S Raffaele, Milano
1997-2002: Director, Medical Genetics Unit, Azienda Ospedaliera Universitaria Senese
2002-date: Director, Molecular Medicine & Genetic Unit, Azienda Ospedaliera Universitaria Senese
2004-2010: Director, Center for Stem Cell Research, University of Siena
2010-2012: Chairman, Department of Neuroscience, University of Siena
2012-date: Director, Molecular Medicine Laboratory, Department of Molecular and Developmental Medicine, University of Siena
2010-date: Vice-Rector for Research, University of Sienaedit
Here, we report the identification of three novel missense mutations in the calsequestrin-1
A novel FLNC c.5161delG (p.Gly1722ValfsTer61) mutation was identified in two members of a French family affected by distal myopathy and in one healthy relative. This FLNC c.5161delG mutation is one nucleotide away from a previously... more
A novel FLNC c.5161delG (p.Gly1722ValfsTer61) mutation was identified in two members of a French family affected by distal myopathy and in one healthy relative. This FLNC c.5161delG mutation is one nucleotide away from a previously reported FLNC mutation (c.5160delC) that was identified in patients and in asymptomatic carriers of three Bulgarian families with distal muscular dystrophy, indicating a low penetrance of the FLNC frameshift mutations. Given these similarities, we believe that the two FLNC mutations alone can be causative of distal myopathy without full penetrance. Moreover, comparative analysis of the clinical manifestations indicates that patients of the French family show an earlier onset and a complete segregation of the disease. As a possible explanation of this, the two French patients also carry a OBSCN c.13330C>T (p.Arg4444Trp) mutation. The p.Arg4444Trp variant is localized within the OBSCN Ig59 domain that, together with Ig58, binds to the ZIg9/ ZIg10 domains of titin at Z-disks. Structural and functional studies indicate that this OBSCN p.Arg4444Trp mutation decreases titin binding by ~15-fold. On this line, we suggest that the combination of the OBSCN p.Arg4444Trp variant and of the FLNC c.5161delG mutation, can cooperatively affect myofibril stability and increase the penetrance of muscular dystro-phy in the French family.
Point mutations in the ryanodine receptor (RYR1) gene are associated with malignant hyperthermia, an autosomal dominant disorder triggered in susceptible people (MHS) by volatile anaesthetics and depolarising skeletal muscle relaxants. To... more
Point mutations in the ryanodine receptor (RYR1) gene are associated with malignant hyperthermia, an autosomal dominant disorder triggered in susceptible people (MHS) by volatile anaesthetics and depolarising skeletal muscle relaxants. To date, 17 missense point mutations have been identified in the human RYR1 gene by screening of the cDNA obtained from muscle biopsies. Here we report single strand conformation polymorphism (SSCP) screening for nine of the most frequent RYR1 mutations using genomic DNA isolated from MHS patients. In addition, the Argl63Cys mutation was analysed by restriction enzyme digestion. We analysed 57 unrelated patients and detected seven of the known RYR1 point mutations. Furthermore, we found a new mutation, Arg2454His, segregating with the MHS phenotype in a large pedigree and a novel amino acid substitution at position 2436 in another patient, indicating a 15.8% frequency of these mutations in Italian patients. A new polymorphic site in intron 16 that cau...
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To define the relationship between the two ryanodine receptor (RyR) isoforms present in chicken skeletal muscle, we cloned two groups of cDNAs encoding the chicken homologues of mammalian RyR1 and RyR3. Equivalent amounts of the two... more
To define the relationship between the two ryanodine receptor (RyR) isoforms present in chicken skeletal muscle, we cloned two groups of cDNAs encoding the chicken homologues of mammalian RyR1 and RyR3. Equivalent amounts of the two chicken isoform mRNAs were detected in thigh and pectoral skeletal muscles. RyR1 and RyR3 mRNAs were co-expressed in testis and cerebellum whereas RyR3 mRNA was expressed also in the cerebrum and heart. The full-length sequence of the chicken RyR3 cDNA was established. The RyR3 receptor from chicken had the same general structure as mammalian and amphibian RyRs. The 15089 nt cDNA encoded a 4869-amino-acid-long protein with a molecular mass of 552445. The predicted amino acid sequence of the chicken RyR3 showed 86.9% identity to mammalian RyR3 and 85.6% to frog RyR3. Antibodies specific for chicken RyR1 and RyR3 recognized two different proteins with an apparent molecular mass of about 500 kDa. The two proteins differ slightly in their apparent molecular ...
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Activation of intracellular Ca(2+)-release channels/ryanodine receptors (RyRs) is a fundamental step in the regulation of muscle contraction. In mammalian skeletal muscle, Ca(2+)-release channels containing the type 1 isoform of RyR... more
Activation of intracellular Ca(2+)-release channels/ryanodine receptors (RyRs) is a fundamental step in the regulation of muscle contraction. In mammalian skeletal muscle, Ca(2+)-release channels containing the type 1 isoform of RyR (RyR1) open to release Ca2+ from the sarcoplasmic reticulum (SR) upon stimulation by the voltage-activated dihydropyridine receptor on the T-tubule/plasma membrane. In addition to RyR1, low levels of the mRNA of the RyR3 isoform have been recently detected in mammalian skeletal muscles. Here we report data on the distribution of the RyR3 gene product in mammalian skeletal muscles. Western-blot analysis of SR of individual muscles indicated that, at variance with the even distribution of the RyR1 isoform, the RyR3 content varies among different muscles, with relatively higher amounts being detected in diaphragm and soleus, and lower levels in abdominal muscles and tibialis anterior. In these muscles RyR3 was localized in the terminal cisternae of the SR. ...
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An interleukin-3 (IL-3) dependent mast cell line (MC) was infected with a recombinant retrovirus expressing the proto-oncogene c-myc and the drug selectable marker neo. Cells containing the transcriptionally activated c-myc gene displayed... more
An interleukin-3 (IL-3) dependent mast cell line (MC) was infected with a recombinant retrovirus expressing the proto-oncogene c-myc and the drug selectable marker neo. Cells containing the transcriptionally activated c-myc gene displayed an increased growth rate in liquid culture and a higher cloning efficiency in soft agar when compared to control virus infected cells. All infected cells remained absolutely dependent on IL-3 for growth and were not tumorigenic in nude mice. Similar results were obtained with two additional IL-3 dependent cell lines, the mast cell 32D and the pre-B-cell Ea3. Thus, while constitutive expression of c-myc potentiates the response of mast cells to IL-3, it is not sufficient to eliminate their requirement for growth factors.
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Mouse C3H10T1/2 cells were co-transfected with a plasmid containing the KiSV DNA and a plasmid carrying sequences coding for resistance to mycophenolic acid. Only 30% of the transfected colonies had a transformed phenotype, i.e. highly... more
Mouse C3H10T1/2 cells were co-transfected with a plasmid containing the KiSV DNA and a plasmid carrying sequences coding for resistance to mycophenolic acid. Only 30% of the transfected colonies had a transformed phenotype, i.e. highly refractile rounded cells. The remaining colonies had varied morphologies with flat or slightly elongated cells. Analysis of p21 ras protein indicated that higher levels of the protein were expressed in cells with the more transformed phenotype. Tumors formed by a poorly tumorigenic clone were found to have undergone in vivo amplification of the transfected KiSV sequence. Transformed variants of this clone were also isolated in vitro. Treatment with 5-azacytidine resulted in an increase of about 10 fold in the formation of transformed variants. All transformed cells isolated, either spontaneous or 5-azacytidine induced, were tumorigenic in nude mice. The neoplastic conversion of these cells was accompanied by amplification of the transfected K-ras sequ...
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Decisions about growth or quiescence are operated in the cells by a complex signal processing machinery. This machinery is built by a network of proteins that internalize these stimulatory signals from the extracellular environment across... more
Decisions about growth or quiescence are operated in the cells by a complex signal processing machinery. This machinery is built by a network of proteins that internalize these stimulatory signals from the extracellular environment across the plasmamembrane, through the cytoplasm and finally into the nucleus. Most of the information about the genes which encode the proteins that take part in this process have been obtained from studies of their aberrant alleles or oncogenes. It has become clear lately that the cell also processes negative feedback mechanisms to check this process so that it may operate error free.
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ABSTRACT
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Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The... more
Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca2+ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers. In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca2+ release from sarcoplasmic reticulum (SR) were studied in vitro. A total of 200 patients met the inclusion criteria. Two MH crises (1%) were triggered by SCh (1 MHS, 1 MHE), 18% by volatile anesthetics and 81% by a combination of both. Patients were 70% male and 50% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca2+ release from isolated rat SR vesicles. An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca2+ release. SCh might act as an accelerant by promoting unspecific Ca2+ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.
Research Interests: Adolescent, Humans, Child, Mutation, Female, and 6 moreMale, Young Adult, Infant, Middle Aged, Adult, and Malignant Hyperthermia
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Ryanodine receptors are intracellular Ca2+ channels that have been known for more than a decade to have a role in releasing Ca2+ from the sarcoplasmic reticulum to regulate contraction in skeletal and cardiac muscle fibres. Vincenzo... more
Ryanodine receptors are intracellular Ca2+ channels that have been known for more than a decade to have a role in releasing Ca2+ from the sarcoplasmic reticulum to regulate contraction in skeletal and cardiac muscle fibres. Vincenzo Sorrentino and Pompeo Volpe review some recent developments: the ryanodine receptor channels have now been found to be expressed in the central nervous system, and the cloning of a third ryanodine receptor gene (RYR3) has revealed that this new isoform is widely expressed in several tissues and cells. In consequence, the view of ryanodine receptors as Ca2+ channels of muscle cells is rapidly changing, and these channels seem set to take a more central position on the stage of intracellular Ca2+ signalling.
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Mobilization of Ca2+ from the endoplasmic reticulum (ER) is mediated by two related groups of Ca2+ release channels, the inositol 1,4,5 trisphosphate (InsP3) receptors and the ryanodine receptors. The InsP3 receptors have been studied in... more
Mobilization of Ca2+ from the endoplasmic reticulum (ER) is mediated by two related groups of Ca2+ release channels, the inositol 1,4,5 trisphosphate (InsP3) receptors and the ryanodine receptors. The InsP3 receptors have been studied in a large number of cells where they regulate many different activities upon stimulation with a variety of agonists. Ryanodine receptors have been essentially studied with respect to their role in regulating muscle contraction in both cardiac and skeletal muscles. In the recent years, InsP3 receptors and ryanodine receptors have been found to be co-expressed in neurons and other cell types, including smooth muscle cells. This emerging picture reveals that within one cell different combinations of two or more isoforms of Ca2+ release channels (i.e., multiple InsP3 receptors and/or ryanodine receptors) can be expressed at the same time. New data on the expression of two isoforms of ryanodine receptors in developing skeletal muscles or in specialized adult muscles have provided initial ground to test the hypothesis that combinations of various Ca2+ release channels may be relevant to adapt the modality of Ca2+ release to regulation of specific cellular functions.