277 results on '"Salviati L"'
Search Results
2. Specific heterozygous frameshift variants in hnRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy
- Author
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Ambegaonkar G, Evangelista T, Maura Coughlin, O’Donovan Dg, Mark A. Tarnopolsky, Tobias B. Haack, Sarah Ennis, Foley Ar, Shatillo A, Zaharieva It, Lornage X, Sato A, Sandra Donkervoort, Nelson I, Grimmel M, Salviati L, Francesco Muntoni, Bello L, Lauren Brady, James Shorter, Iida A, Böhm J, Maja Steinlin, Ana Töpf, Ichizo Nishino, Péréon Y, Quijano-Roy S, Carsten G. Bönnemann, Ogasawara M, Hu Y, Alice Flynn Ford, Klein A, Kevin J. O'Donovan, Raymond Fl, Kuster A, Marcorelles P, Adnan Y. Manzur, Buchert R, Charlotte M. Fare, Hammans, Romero Nb, Munot P, Bertolin C, Upstill-Goddard R, Mercier S, Stojkovic T, Thomas E. Lloyd, Fleurence E, Lin Guo, Courtney E. French, Phadke R, Laporte J, Taylor Jp, Payam Mohassel, Straub, Elena Pegoraro, Hong Joo Kim, and Foulds N
- Subjects
Genetics ,medicine ,Missense mutation ,Muscular dystrophy ,Amyotrophic lateral sclerosis ,medicine.symptom ,Biology ,medicine.disease ,Myopathy ,Phenotype ,Frameshift mutation ,Frontotemporal dementia ,Oculopharyngeal muscular dystrophy - Abstract
SummaryRNA-binding proteins (RBPs) are essential for post-transcriptional regulation and processing of RNAs. Pathogenic missense variants in RBPs underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, inclusion body myopathy, distal myopathy, and Paget’s disease of the bone. Here, we present ten independent families with a severe, progressive, early-onset muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD), caused by heterozygous frameshift variants in the prion-like domain of hnRNPA2B1. We found that in contrast with the previously reported missense variants, the frameshift hnRNPA2B1 variants do not promote, but rather decelerate the fibrillization of the protein. Importantly, the frameshift variants harbor altered nuclear-localization sequences and exhibit reduced affinity for the nuclear-import receptor, Karyopherin-β2, which promotes their cytoplasmic accumulation in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with hnRNPA2B1 to include a severe, early-onset disease reminiscent of OPMD, caused by a distinct class of frameshift variants that alter its nucleocytoplasmic transport dynamics.
- Published
- 2021
3. Maturation signatures of conventional dendritic cell subtypes in COVID-19 reflect direct viral sensing
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Mariacristina Crosti, Mihai Valache, Francesca Granucci, Fabio A. Facchini, Salviati L, Serena Curti, Mariella D'Angiò, Protti G, Nicola Clementi, Nicolò Tamini, Roberto Spreafico, Laura Marongiu, Andrea Biondi, Sergio Abrignani, Anna Rita Putignano, Laura Rachele Bettini, Ranzani, Francesca Mingozzi, Nicasio Mancini, Luca Nespoli, and Bevilacqua
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Cyclin-dependent kinase 1 ,medicine.anatomical_structure ,Immune system ,Effector ,T cell ,Antigen presentation ,medicine ,Signal transduction ,Biology ,In vitro ,Cell biology ,Proinflammatory cytokine - Abstract
Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19 and this negatively affects T cell activation. The presence of functional effector T cells in mild patients and dysfunctional T cells in severely ill patients suggests that adequate T cell responses are needed to limit disease severity. Therefore, understanding how cDCs cope with SARS-CoV-2 infections can help elucidate the mechanism of generation of protective immune responses. Here, we report that cDC2 subtypes exhibit similar infection-induced gene signatures with the up-regulation of interferon-stimulated genes and IL-6 signaling pathways. The main difference observed between DC2s and DC3s is the up-regulation of anti-apoptotic genes in DC3s, which explains their accumulation during infection. Furthermore, comparing cDCs between severe and mild patients, we find in the former a profound down-regulation of genes encoding molecules involved in antigen presentation, such as major histocompatibility complex class II (MHCII) molecules, β2 microglobulin, TAP and costimulatory proteins, while an opposite trend is observed for proinflammatory molecules, such as complement and coagulation factors. Therefore, as the severity of the disease increases, cDC2s enhance their inflammatory properties and lose their main function, which is the antigen presentation capacity. In vitro, direct exposure of cDC2s to the virus recapitulates the type of activation observed in vivo. Our findings provide evidence that SARS-CoV-2 can interact directly with cDC2s and, by inducing the down-regulation of crucial molecules required for T cell activation, implements an efficient immune escape mechanism that correlates with disease severity.
- Published
- 2021
4. Neurofibromatosis type 1 in two siblings due to maternal germline mosaicism
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Trevisson, E., Forzan, M., Salviati, L., and Clementi, M.
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- 2014
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5. Diagnosis, genetic characterization and clinical follow up of mitochondrial fatty acid oxidation disorders in the new era of expanded newborn screening: A single centre experience
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Maguolo, A., primary, Rodella, G., additional, Dianin, A., additional, Nurti, R., additional, Monge, I., additional, Rigotti, E., additional, Cantalupo, G., additional, Salviati, L., additional, Tucci, S., additional, Pellegrini, F., additional, Molinaro, G., additional, Lupi, F., additional, Tonin, P., additional, Pasini, A., additional, Campostrini, N., additional, Ion Popa, F., additional, Teofoli, F., additional, Vincenzi, M., additional, Camilot, M., additional, Piacentini, G., additional, and Bordugo, A., additional
- Published
- 2020
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6. hCOX18 and hCOX19, two new human genes involved in Cytochrome c oxydase assembly: SC314
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Sacconi, S., Salviati, L., DiMauro, S., and Desnuelle, C.
- Published
- 2005
7. Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence
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Tezze, C, Romanello, V, Desbats, Ma, Fadini, Gp, Albiero, M, Favaro, G, Ciciliot, S, Soriano, Me, Morbidoni, V, Cerqua, C, Loefler, S, Kern, H, FRANCESCHI, CLAUDIO, SALVIOLI, STEFANO, CONTE, MARIA, Blaauw, B, Zampieri, S, Salviati, L, Scorrano, L, Sandri, M., Tezze, C, Romanello, V, Desbats, Ma, Fadini, Gp, Albiero, M, Favaro, G, Ciciliot, S, Soriano, Me, Morbidoni, V, Cerqua, C, Loefler, S, Kern, H, Franceschi, C, Salvioli, S, Conte, M, Blaauw, B, Zampieri, S, Salviati, L, Scorrano, L, and Sandri, M.
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mitochondria ,sarcopenia ,endocrine system ,oxidative stre ,FGF21 ,inflammation ,muscle ,aging ,FoxO ,Opa1 ,eye diseases - Abstract
Mitochondrial dysfunction occurs during aging, but its impact on tissue senescence is unknown. Here, we find that sedentary but not active humans display an age-related decline in the mitochondrial protein, optic atrophy 1 (OPA1), that is associated with muscle loss. In adult mice, acute, muscle-specific deletion of Opa1 induces a precocious senescence phenotype and premature death. Conditional and inducible Opa1 deletion alters mitochondrial morphology and function but not DNA content. Mechanistically, the ablation of Opa1 leads to ER stress, which signals via the unfolded protein response (UPR) and FoxOs, inducing a catabolic program of muscle loss and systemic aging. Pharmacological inhibition of ER stress or muscle-specific deletion of FGF21 compensates for the loss of Opa1, restoring a normal metabolic state and preventing muscle atrophy and premature death. Thus, mitochondrial dysfunction in the muscle can trigger a cascade of signaling initiated at the ER that systemically affects general metabolism and aging.
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- 2017
8. Mutations in COQ8B found in patients with steroid-resistant nephrotic syndrome Alter COQ8B function
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Vazquez-Fonseca, L., Doimo, M., Calderan, C., Desbats, M. A., Acosta, M. J., Cerqua, C., Cassina, M., Ashraf, S., Hildebrandt, Friedhelm, Sartori, G., Navas, Plácido, Trevisson, E., and Salviati, L.
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food and beverages - Abstract
Resumen del póster presentado a la XI Reunión Anual CIBERER, celebrada en Castelldefels, Barcelona del 12 al 14 de marzo de 2018., The coenzyme Q (CoQ) biosynthesis pathway has been well studied in yeast and comprises at least 12 COQ genes. COQ8 encodes an atypical protein kinase that appears to be essential for the phosphorylation of several Coq polypeptides. Yeast COQ8 mutants lack CoQ and are not able to growth in non-fermentable carbon media sources as glycerol. Humans harbor two paralog genes of COQ8; COQ8A and COQ8B (previously termed ADCK3 and ADCK4). Mutations in COQ8B cause steroid-resistant nephrotic syndrome with variable neurological involvement. We have found that COQ8B is a mitochondrial matrix protein peripherally associated with the inner membrane with a similar behavior to other COQ proteins like COQ4 and COQ5. Moreover, COQ8B can complement a COQ8 yeast null strain when its mitochondrial targeting sequence (MTS) is replaced by either the yCOQ3 or yCOQ8 MTS, but not when the MTS was simply added to the N-terminus. This model was employed to validate COQ8B mutations, and to establish genotype–phenotype correlations. All mutations affected respiratory growth, but there was no correlation between mutation type and the severity of the phenotype. These data also suggest that the system is redundant, and that other proteins (probably COQ8A) may partially compensate for the absence of COQ8B. Finally, a COQ8B polymorphism, present in 50% of the European population (NM_024876.3:c.521A > G, p.His174Arg), affects stability of the protein and could represent a risk factor for secondary CoQ deficiencies.
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- 2018
9. Molecular diagnosis of coenzyme Q(10) deficiency: an update
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Yubero-Siles D, Montero-Sanchez R, Santos-Ocaña C, Salviati L, Navas P, and Artuch-Iriberri R
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next generation sequencing ,mitochondrial diseases ,Coenzyme Q(10) deficiency syndromes ,oxidative phosphorylation ,food and beverages ,muscle biopsy ,Coenzyme Q10 deficiency syndromes - Abstract
Coenzyme Q(10) (CoQ) deficiency syndromes comprise a growing number of genetic disorders. While primary CoQ deficiency syndromes are rare diseases, secondary deficiencies have been related to both genetic and environmental conditions, which are the main causes of biochemical CoQ deficiency. The diagnosis is the essential first step for planning future treatment strategies, as the potential treatability of CoQ deficiency is the most critical issue for the patients. Areas covered: While the quickest and most effective tool to define a CoQ-deficient status is its biochemical determination in biological fluids or tissues, this quantification does not provide a definite diagnosis of a CoQ-deficient status nor insight about the genetic etiology of the disease. The different laboratory tests to check for CoQ deficiency are evaluated in order to choose the best diagnostic pathway for the patient. Expert commentary: New insights are being discovered about the implication of new proteins in the intricate CoQ biosynthetic pathway. These insights reinforce the idea that next generation sequencing diagnostic strategies are the unique alternative in terms of rapid and accurate molecular diagnosis of CoQ deficiency.
- Published
- 2018
10. Further phenotypic heterogeneity of CoQ10 deficiency associated with Steroid Resistant Nephrotic Syndrome and novel COQ2 and COQ6 variants
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Gigante, M., Diella, S., Santangelo, L., Trevisson, E., Acosta, M. J., Amatruda, M., Finzi, G., Caridi, G., Murer, L., Accetturo, M., Ranieri, E., Ghiggeri, G. M., Giordano, M., Grandaliano, Giuseppe, Salviati, L., and Gesualdo, L.
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Male ,Mitochondrial Diseases ,Muscle Weakness ,Nephrotic Syndrome ,Ubiquinone ,DNA Mutational Analysis ,COQ2 ,yeast model ,COQ6 ,Pedigree ,Coenzyme Q10 deficiency ,Mutation ,Humans ,Settore MED/14 - NEFROLOGIA ,Ataxia ,Computer Simulation ,Female ,Steroid Resistant Nephrotic Syndrome - Published
- 2017
11. Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q(10) content
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Asencio C, Rodríguez-Hernandez MA, Briones P, Montoya J, Cortés A, Emperador S, Gavilán A, Ruiz-Pesini E, Yubero-Siles D, Montero-Sanchez R, Pineda M, O'Callaghan-Gordo M, Alcázar-Fabra M, Salviati L, Artuch-Iriberri R, and Navas P
- Abstract
Coenzyme Q(10) (CoQ(10)) deficiency is associated to a variety of clinical phenotypes including neuromuscular and nephrotic disorders. We report two unrelated boys presenting encephalopathy, ataxia, and lactic acidosis, who died with necrotic lesions in different areas of brain. Levels of CoQ(10) and complex II+III activity were increased in both skeletal muscle and fibroblasts, but it was a consequence of higher mitochondria mass measured as citrate synthase. In fibroblasts, oxygen consumption was also increased, whereas steady state ATP levels were decreased. Antioxidant enzymes such as NQO1 and MnSOD and mitochondrial marker VDAC were overexpressed. Mitochondria recycling markers Fis1 and mitofusin, and mtDNA regulatory Tfam were reduced. Exome sequencing showed mutations in PDHA1 in the first patient and in PDHB in the second. These genes encode subunits of pyruvate dehydrogenase complex (PDH) that could explain the compensatory increase of CoQ(10) and a defect of mitochondrial homeostasis. These two cases describe, for the first time, a mitochondrial disease caused by PDH defects associated with unbalanced of both CoQ(10) content and mitochondria homeostasis, which severely affects the brain. Both CoQ(10) and mitochondria homeostasis appears as new markers for PDH associated mitochondrial disorders.
- Published
- 2016
12. Further phenotypic heterogeneity of CoQ10 deficiency associated with steroid resistant nephrotic syndrome and novel COQ2 and COQ6 variants
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Gigante, M., primary, Diella, S., additional, Santangelo, L., additional, Trevisson, E., additional, Acosta, M.J., additional, Amatruda, M., additional, Finzi, G., additional, Caridi, G., additional, Murer, L., additional, Accetturo, M., additional, Ranieri, E., additional, Ghiggeri, G.M., additional, Giordano, M., additional, Grandaliano, G., additional, Salviati, L., additional, and Gesualdo, L., additional
- Published
- 2017
- Full Text
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13. Molecular diagnosis of coenzyme Q(10) deficiency
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Yubero-Siles D, Montero-Sanchez R, Armstrong-Moron J, Espinós C, Palau F, Santos-Ocaña C, Salviati L, Navas P, and Artuch-Iriberri R
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mitochondrial diseases ,next-generation sequencing ,muscle biopsy ,coenzyme Q10 deficiency syndromes ,functional studies in yeasts - Abstract
Coenzyme Q(10) (CoQ) deficiency syndromes comprise a growing number of neurological and extraneurological disorders. Primary-genetic but also secondary CoQ deficiencies have been reported. The biochemical determination of CoQ is a good tool for the rapid identification of CoQ deficiencies but does not allow the selection of candidate genes for molecular diagnosis. Moreover, the metabolic pathway for CoQ synthesis is an intricate and not well-understood process, where a large number of genes are implicated. Thus, only next-generation sequencing techniques (either genetic panels of whole-exome and -genome sequencing) are at present appropriate for a rapid and realistic molecular diagnosis of these syndromes. The potential treatability of CoQ deficiency strongly supports the necessity of a rapid molecular characterization of patients, since primary CoQ deficiencies may respond well to CoQ treatment.
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- 2015
14. Development of optimized assays for mitochondrial respiratory chain enzymatic activities in tissues and cells
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Spinazzi, M., Casarin, A., Salviati, L., and Corrado Angelini
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- 2012
15. Coenzyme Q10 distribution in blood is altered in patients with Fibromyalgia
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Cordero, M.D., Moreno-Fernández, A.M., deMiguel, M., Bonal, P., Campa, F., Jiménez-Jiménez, L.M., Ruiz-Losada, A., Sánchez-Domínguez, B., Sánchez Alcázar, J.A., Salviati, L., and Navas, P.
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- 2009
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16. Neurofibromatosis type 1 in two siblings due to maternal germline mosaicism
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Trevisson, E., primary, Forzan, M., additional, Salviati, L., additional, and Clementi, M., additional
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- 2013
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17. Genetic susceptibility to teratogens: State of the art
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Cassina, M., primary, Salviati, L., additional, Di Gianantonio, E., additional, and Clementi, M., additional
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- 2012
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18. Genetic studies in renal diseases
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Tosetto, E., primary, Casarin, A., additional, Cristofaro, R., additional, Salviati, L., additional, Anglani, F., additional, Prot Bertoye, C., additional, Lebbah, S., additional, Daudon, M., additional, Couffignal, C., additional, Elie, C., additional, Tostivint, I., additional, Traxer, O., additional, Knebelmann, B., additional, Courbebaisse, M., additional, Bavbek Ruzgaresen, N., additional, Ceri, M., additional, Kargili, A., additional, Akdeniz, D., additional, Akcay, A., additional, Duranay, M., additional, Guz, G., additional, Testa, A., additional, Spoto, B., additional, Sanguedolce, M. C., additional, Panuccio, V., additional, Leonardis, D., additional, Tripepi, R., additional, Mafrica, A., additional, Tripepi, G., additional, Zoccali, C., additional, Mallamaci, F., additional, Pesce, F., additional, Cox, S. N., additional, Serino, G., additional, Sallustio, F., additional, Froguel, P., additional, Schena, F. P., additional, Falchi, M., additional, Boger, C., additional, and Ckd Progression Writing Group, O. B. o. t. C., additional
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- 2012
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19. Development of Optimized Assays for Mitochondrial Respiratory Chain Enzymatic Activities in Muscle and Cells (P07.212)
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Spinazzi, M., primary, Casarin, A., additional, Pertegato, V., additional, Salviati, L., additional, and Angelini, C., additional
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- 2012
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20. Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia
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Occhi, G, primary, Trivellin, G, additional, Ceccato, F, additional, De Lazzari, P, additional, Giorgi, G, additional, Demattè, S, additional, Grimaldi, F, additional, Castello, R, additional, Davì, M V, additional, Arnaldi, G, additional, Salviati, L, additional, Opocher, G, additional, Mantero, F, additional, and Scaroni, C, additional
- Published
- 2010
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21. SEVERE CMT TYPE 2 WITH FATAL ENCEPHALOPATHY ASSOCIATED WITH A NOVEL MFN2 SPLICING MUTATION
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Boaretto, F., primary, Vettori, A., additional, Casarin, A., additional, Vazza, G., additional, Muglia, M., additional, Rossetto, M. G., additional, Cavallaro, T., additional, Rizzuto, N., additional, Carelli, V., additional, Salviati, L., additional, Mostacciuolo, M. L., additional, and Martinuzzi, A., additional
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- 2010
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22. A functionally dominant mitochondrial DNA mutation
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Sacconi, S., primary, Salviati, L., additional, Nishigaki, Y., additional, Walker, W. F., additional, Hernandez-Rosa, E., additional, Trevisson, E., additional, Delplace, S., additional, Desnuelle, C., additional, Shanske, S., additional, Hirano, M., additional, Schon, E. A., additional, Bonilla, E., additional, De Vivo, D. C., additional, DiMauro, S., additional, and Davidson, M. M., additional
- Published
- 2008
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23. LETM1, deleted in Wolf Hirschhorn syndrome is required for normal mitochondrial morphology and cellular viability
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Dimmer, K. S., primary, Navoni, F., additional, Casarin, A., additional, Trevisson, E., additional, Endele, S., additional, Winterpacht, A., additional, Salviati, L., additional, and Scorrano, L., additional
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- 2007
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24. M.P.3.12 Characterization of COX16, a novel human gene required for cytochrome c oxidase assembly
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Sacconi, S., primary, Trevisson, E., additional, Casarin, A., additional, Salviati, L., additional, and Desnuelle, C., additional
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- 2007
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25. Renal hypoplasia without optic coloboma associated with PAX2 gene deletion
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Benetti, E., primary, Artifoni, L., additional, Salviati, L., additional, Pinello, L., additional, Perrotta, S., additional, Zuffardi, O., additional, Zacchello, G., additional, and Murer, L., additional
- Published
- 2007
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26. M - 15 C5545T : une mutation dominante d’un ARN de transfert (ARNt) mitochondrial humain induisant un « saut du codon stop »
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Sacconi, S., primary, Salviati, L., additional, DiMauro, S., additional, DeViVo, D., additional, Davidson, M., additional, and Desnuelle, C., additional
- Published
- 2007
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27. Diagnostic challenges in facioscapulohumeral muscular dystrophy
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Sacconi, S., primary, Salviati, L., additional, Bourget, I., additional, Figarella, D., additional, Pereon, Y., additional, Lemmers, R., additional, van der Maarel, S., additional, and Desnuelle, C., additional
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- 2006
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28. Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: A CoQ10-responsive condition
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Salviati, L., primary, Sacconi, S., additional, Murer, L., additional, Zacchello, G., additional, Franceschini, L., additional, Laverda, A. M., additional, Basso, G., additional, Quinzii, C., additional, Angelini, C., additional, Hirano, M., additional, Naini, A. B., additional, Navas, P., additional, DiMauro, S., additional, and Montini, G., additional
- Published
- 2005
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29. Mitochondrial myopathy and ophthalmoplegia in a sporadic patient with the G12315A mutation in mitochondrial DNA
- Author
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KARADIMAS, C, primary, SALVIATI, L, additional, SACCONI, S, additional, CHRONOPOULOU, P, additional, SHANSKE, S, additional, BONILLA, E, additional, DEVIVO, D, additional, and DIMAURO, S, additional
- Published
- 2002
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30. Mitochondrial DNA depletion
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Mancuso, M., primary, Salviati, L., additional, Sacconi, S., additional, Otaegui, D., additional, Camaño, P., additional, Marina, A., additional, Bacman, S., additional, Moraes, C.T., additional, Carlo, J.R., additional, Garcia, M., additional, Garcia-Alvarez, M., additional, Monzon, L., additional, Naini, A.B., additional, Hirano, M., additional, Bonilla, E., additional, Taratuto, A.L., additional, DiMauro, S., additional, and Vu, T.H., additional
- Published
- 2002
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31. Acute disseminated encephalomyelitis associated with hepatitis C virus infection (Arch. Neurol. — 2001. — Oct. — 58(10). — P. 1679—1681: англ.)
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Sacconi, S., primary, Salviati, L., additional, and Merelli, E., additional
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- 2001
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32. Le Spondilodisciti in età pediatrica
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Salviati, L., primary, Monciotti, C., additional, Turra, S., additional, Gigante, C., additional, Dei Rossi, A., additional, Amistà, P., additional, and Carollo, C., additional
- Published
- 1998
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33. Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.
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Mancuso, M, Salviati, L, Sacconi, S, Otaegui, D, Camaño, P, Marina, A, Bacman, S, Moraes, C T, Carlo, J R, Garcia, M, Garcia-Alvarez, M, Monzon, L, Naini, A B, Hirano, M, Bonilla, E, Taratuto, A L, DiMauro, S, and Vu, T H
- Published
- 2002
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34. Diencephalic syndrome and disseminated juvenile pilocytic astrocytomas of the hypothalamic-optic chiasm region.
- Author
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Perilongo, Giorgio, Carollo, Carla, Salviati, Leonardo, Murgia, Alessandra, Pillon, Marta, Basso, Giuseppe, Gardiman, Marina, Laverda, AnnaMaria, Perilongo, G, Carollo, C, Salviati, L, Murgia, A, Pillon, M, Basso, G, Gardiman, M, and Laverda, A
- Published
- 1997
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35. Le Spondilodisciti in età pediatrica: Presentazione di 7 casi
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Salviati, L., Monciotti, C., Turra, S., Gigante, C., Dei Rossi, A., Amistà, P., and Carollo, C.
- Abstract
La spondilodiscite è un processo infiammatorio a carico del disco vertebrale con variabile interessamento dell'osso confinante. è una patologia, benché rara, tipica dell'età pediatrica, la cui reale incidenza non è nota. L'eziologia è infettiva nella maggior parte dei casi, i segmenti più colpiti sono soprattutto le vertebre lombari, la via di diffusione è per lo più ematogena, a differenza delle forme dell'adulto, prevalentemente secondarie a manovre chirurgiche. La ricca vascolarizzazione disco-vertebrale nell'infanzia rende conto delle peculiari caratteristiche di questa patologia. I sintomi iniziali sono spesso aspecifici (febbre, dolore, disturbi della deambulazione), rara la leucocitosi, quasi costante l'elevazione degli indici di flogosi, emocoltura positiva in meno del 30% dei casi. 7 casi seguiti presso il nostro centro negli ultimi 8 anni. La diagnosi è stata posta mediante radiologia tradizionale, TC, RM in tutti i casi, e in 3 pazienti anche con biopsia TC-mirata, con follow up da 1 a 10 anni.La spondilodiscite in età pediatrica è una patologia a prognosi favorevole, la RM è determinante per la diagnosi, il controllo a distanza è indicato per la valutazione degli esiti: ridotto accrescimento encondrale, cifosi focale, fusione intervertebrale.
- Published
- 1998
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36. SEVERE CMT TYPE 2 WITH FATAL ENCEPHALOPATHY ASSOCIATED WITH A NOVEL MFN2SPLICING MUTATION
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Boaretto, F., Vettori, A., Casarin, A., Vazza, G., Muglia, M., Rossetto, M.G., Cavallaro, T., Rizzuto, N., Carelli, V., Salviati, L., Mostacciuolo, M.L., and Martinuzzi, A.
- Published
- 2010
- Full Text
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37. Acute quadriplegic myopathy in a 17-month-old-boy
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Salviati, L., Laverda, A. M., Zancan, L., Fanin, M., Corrado Angelini, and Meznaric-Petrusa, M.
38. The COQ2 genotype predicts the severity of coenzyme Q10 deficiency
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Andrea Desbats M, Morbidoni V, Silic-Benussi M, Doimo M, Ciminale V, Cassina M, Sacconi S, Hirano M, Basso G, Fabien Pierrel, Navas P, Salviati L, and Trevisson E
39. Comparative assessment of respiratory chain and antioxidant enzymatic methods in skeletal muscle biopsies
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Spinazzi, M., Casarin, A., Salviati, L., and Corrado Angelini
40. Gene symbol: ASL. Disease: Argininosuccinate lyase deficiency
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Trevisson, E., Salviati, L., Baldoin, M. C., Casarin, A., GIUSEPPE BASSO, and Burlina, A.
41. Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with sco2 mutations
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Casarin Alberto, Giorgi Gianpietro, Pertegato Vanessa, Siviero Roberta, Cerqua Cristina, Doimo Mara, Basso Giuseppe, Sacconi Sabrina, Cassina Matteo, Rizzuto Rosario, Brosel Sonja, M Davidson Mercy, DiMauro Salvatore, Schon Eric A, Clementi Maurizio, Trevisson Eva, and Salviati Leonardo
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COX deficiency ,Bezafibrate ,SCO2 ,Copper chaperones ,Copper supplementation ,Medicine - Abstract
Abstract Background Mutations in SCO2 cause cytochrome c oxidase deficiency (COX) and a fatal infantile cardioencephalomyopathy. SCO2 encodes a protein involved in COX copper metabolism; supplementation with copper salts rescues the defect in patients’ cells. Bezafibrate (BZF), an approved hypolipidemic agent, ameliorates the COX deficiency in mice with mutations in COX10, another COX-assembly gene. Methods We have investigated the effect of BZF and copper in cells with SCO2 mutations using spectrophotometric methods to analyse respiratory chain activities and a luciferase assay to measure ATP production.. Results Individual mitochondrial enzymes displayed different responses to BZF. COX activity increased by about 40% above basal levels (both in controls and patients), with SCO2 cells reaching 75-80% COX activity compared to untreated controls. The increase in COX was paralleled by an increase in ATP production. The effect was dose-dependent: it was negligible with 100 μM BZF, and peaked at 400 μM BZF. Higher BZF concentrations were associated with a relative decline of COX activity, indicating that the therapeutic range of this drug is very narrow. Combined treatment with 100 μM CuCl2 and 200 μM BZF (which are only marginally effective when administered individually) achieved complete rescue of COX activity in SCO2 cells. Conclusions These data are crucial to design therapeutic trials for this otherwise fatal disorder. The additive effect of copper and BZF will allow to employ lower doses of each drug and to reduce their potential toxic effects. The exact mechanism of action of BZF remains to be determined.
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- 2012
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42. Maturation signatures of conventional dendritic cell subtypes in COVID‐19 suggest direct viral sensing
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Valeria Bevilacqua, Fabio A. Facchini, Roberto Spreafico, Nicasio Mancini, Luca Nespoli, Giulia Protti, Maria Lucia Sarnicola, Valeria Ranzani, Francesca Mingozzi, Andrea Biondi, Serena Curti, Laura Marongiu, Mariella D'Angiò, Mariacristina Crosti, Sergio Abrignani, Francesca Granucci, Laura Rachele Bettini, Anna Rita Putignano, Nicolò Tamini, Lorenzo Salviati, Nicola Clementi, Mihai Valache, Marongiu, Laura, Protti, Giulia, Facchini, Fabio A., Valache, Mihai, Mingozzi, Francesca, Ranzani, Valeria, Putignano, Anna Rita, Salviati, Lorenzo, Bevilacqua, Valeria, Curti, Serena, Crosti, Mariacristina, Sarnicola, Maria Lucia, D'Angiò, Mariella, Bettini, Laura Rachele, Biondi, Andrea, Nespoli, Luca, Tamini, Nicolò, Clementi, Nicola, Mancini, Nicasio, Abrignani, Sergio, Spreafico, Roberto, Granucci, Francesca, Marongiu, L, Protti, G, Facchini, F, Valache, M, Mingozzi, F, Ranzani, V, Putignano, A, Salviati, L, Bevilacqua, V, Curti, S, Crosti, M, Sarnicola, M, D'Angio, M, Bettini, L, Biondi, A, Nespoli, L, Tamini, N, Clementi, N, Mancini, N, Abrignani, S, Spreafico, R, and Granucci, F
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SARS-CoV-2 ,dendritic cell ,Effector ,T-Lymphocytes ,Immunology ,Antigen presentation ,Immunity to infection ,COVID-19 ,Interleukin ,Dendritic Cells ,Biology ,Lymphocyte Activation ,single cell transcriptomics ,Proinflammatory cytokine ,Immune system ,Downregulation and upregulation ,Humans ,Immunology and Allergy ,Research Article|Basic ,Basic ,Signal transduction ,Conventional Dendritic Cell ,Signal Transduction ,Research Article - Abstract
Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID‐19, which negatively affects T‐cell activation. The presence of effector T cells in patients with mild disease and dysfunctional T cells in severely ill patients suggests that adequate T‐cell responses limit disease severity. Understanding how cDCs cope with SARS‐CoV‐2 can help elucidate how protective immune responses are generated. Here, we report that cDC2 subtypes exhibit similar infection‐induced gene signatures, with the upregulation of interferon‐stimulated genes and interleukin (IL)‐6 signaling pathways. Furthermore, comparison of cDCs between patients with severe and mild disease showed severely ill patients to exhibit profound downregulation of genes encoding molecules involved in antigen presentation, such as MHCII, TAP, and costimulatory proteins, whereas we observed the opposite for proinflammatory molecules, such as complement and coagulation factors. Thus, as disease severity increases, cDC2s exhibit enhanced inflammatory properties and lose antigen presentation capacity. Moreover, DC3s showed upregulation of anti‐apoptotic genes and accumulated during infection. Direct exposure of cDC2s to the virus in vitro recapitulated the activation profile observed in vivo. Our findings suggest that SARS‐CoV‐2 interacts directly with cDC2s and implements an efficient immune escape mechanism that correlates with disease severity by downregulating crucial molecules required for T‐cell activation. This article is protected by copyright. All rights reserved
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- 2021
43. The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model
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Charles Kung, Carlo Brugnara, Maria Teresa Valenti, Sebastien Ronseaux, Iana Iatcenko, Tomas Ganz, Anne Janin, Penelope A. Kosinski, Rohini Narayanaswamy, Leonardo Salviati, Achille Iolascon, Francesca Carlomagno, Shaoxia Yu, Giorgia Federico, Enrica Federti, Lucia De Franceschi, Chun-Ling Jung, Alessandro Matte, Roberta Russo, Francesco Michelangelo Turrini, Elisabetta Beneduce, Christophe Leboeuf, Maria Andrea Desbats, Lenny Dang, Università degli studi di Verona = University of Verona (UNIVR), Agios Pharmaceuticals, CEINGE - Biotecnologie Avanzate, University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli Studi di Padova = University of Padua (Unipd), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli studi di Torino = University of Turin (UNITO), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), University of California [Los Angeles] (UCLA), University of California (UC), Harvard Medical School [Boston] (HMS), leboeuf, Christophe, Matte, A., Federti, E., Kung, C., Kosinski, P. A., Narayanaswamy, R., Russo, R., Federico, G., Carlomagno, F., Desbats, M. A., Salviati, L., Leboeuf, C., Valenti, M. T., Turrini, F., Janin, A., Yu, S., Beneduce, E., Ronseaux, S., Iatcenko, I., Dang, L., Ganz, T., Jung, C. -L., Iolascon, A., Brugnara, C., and De Franceschi, L.
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0301 basic medicine ,Ineffective erythropoiesis ,thalassemia ,Enzyme Activator ,Genetic disease ,Quinoline ,medicine.disease_cause ,Mouse models ,Transgenic ,Piperazines ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Glycolysis ,Chemistry ,General Medicine ,Hematology ,Erythroferrone ,Hemolysis ,030220 oncology & carcinogenesis ,Drug therapy ,Genetic diseases ,Animals ,Disease Models, Animal ,Enzyme Activators ,Female ,Mice, Transgenic ,Pyruvate Kinase ,Quinolines ,beta-Thalassemia ,Erythropoiesis ,HAMP ,medicine.drug ,Research Article ,medicine.medical_specialty ,Hemolysi ,[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT] ,Mouse model ,03 medical and health sciences ,Internal medicine ,medicine ,Piperazine ,ineffective erythropoiesis ,[SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT] ,Animal ,medicine.disease ,030104 developmental biology ,Endocrinology ,Erythropoietin ,Disease Models ,iron homeostasis ,Pyruvate kinase - Abstract
International audience; Anemia in β-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired α-globin chains impose substantial oxidative stress on β-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbb th3/+ mouse model for β-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbb th3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in β-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2α axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing β-thalassemia-related liver iron overload. In ex vivo studies on erythroid precursors from patients with β-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for β-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials.
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- 2021
44. Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock
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Thomas O. Eichmann, Mattia Albiero, Alberto Casarin, Michaël Jean Hubert, Vanessa Pertegato, Maximilian Kleinert, Katrin Fischer, Fabiana Quagliarini, Bert Blaauw, Vanina Romanello, S. Mazzucco, Ashfaq Ali Mir, Franziska Greulich, Rosario Rizzuto, Gianni Biolo, Dominik Lutter, Stefano Schiaffino, Leonardo Salviati, Marcia Ivonne Peña Paz, Stefano Ciciliot, Lauren E. Wright, Kenneth A. Dyar, N. Henriette Uhlenhaut, Dyar, K. A., Hubert, M. J., Mir, A. A., Ciciliot, S., Lutter, D., Greulich, F., Quagliarini, F., Kleinert, M., Fischer, K., Eichmann, T. O., Wright, L. E., Pena Paz, M. I., Casarin, A., Pertegato, V., Romanello, V., Albiero, M., Mazzucco, S., Rizzuto, R., Salviati, L., Biolo, G., Blaauw, B., Schiaffino, S., and Uhlenhaut, N. H.
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0301 basic medicine ,Messenger ,Circadian clock ,Protein metabolism ,CLOCK Proteins ,Muscle Proteins ,Gene Expression ,Protein Synthesis ,Biochemistry ,Energy homeostasis ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Medicine and Health Sciences ,Homeostasis ,Biology (General) ,Amino Acids ,Musculoskeletal System ,Protein Metabolism ,Mice, Knockout ,General Neuroscience ,Muscles ,Circadian Clock ,Methods and Resources ,ARNTL Transcription Factors ,Chemical Synthesis ,Skeletal ,11 Medical And Health Sciences ,Lipid ,Lipids ,Cell biology ,Circadian Rhythm ,Amino Acid ,Protein catabolism ,Circadian Oscillators ,medicine.anatomical_structure ,Neuroscience (all) ,Biochemistry, Genetics and Molecular Biology (all) ,Immunology and Microbiology (all) ,Agricultural and Biological Sciences (all) ,ARNTL Transcription Factor ,Muscle ,Anatomy ,General Agricultural and Biological Sciences ,Human ,Muscle Protein Synthesis ,endocrine system ,Biosynthetic Techniques ,QH301-705.5 ,Knockout ,Biology ,Research and Analysis Methods ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Circadian Clocks ,Homeostasi ,medicine ,Genetics ,Animals ,Humans ,CLOCK Protein ,RNA, Messenger ,Muscle, Skeletal ,General Immunology and Microbiology ,Animal ,Protein turnover ,Skeletal muscle ,Correction ,Biology and Life Sciences ,Proteins ,Lipid metabolism ,Metabolism ,06 Biological Sciences ,Lipid Metabolism ,Amino Acid Metabolism ,030104 developmental biology ,chemistry ,Skeletal Muscles ,RNA ,07 Agricultural And Veterinary Sciences ,Chronobiology ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Circadian clocks are fundamental physiological regulators of energy homeostasis, but direct transcriptional targets of the muscle clock machinery are unknown. To understand how the muscle clock directs rhythmic metabolism, we determined genome-wide binding of the master clock regulators brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα in murine muscles. Integrating occupancy with 24-hr gene expression and metabolomics after muscle-specific loss of BMAL1 and REV-ERBα, here we unravel novel molecular mechanisms connecting muscle clock function to daily cycles of lipid and protein metabolism. Validating BMAL1 and REV-ERBα targets using luciferase assays and in vivo rescue, we demonstrate how a major role of the muscle clock is to promote diurnal cycles of neutral lipid storage while coordinately inhibiting lipid and protein catabolism prior to awakening. This occurs by BMAL1-dependent activation of Dgat2 and REV-ERBα-dependent repression of major targets involved in lipid metabolism and protein turnover (MuRF-1, Atrogin-1). Accordingly, muscle-specific loss of BMAL1 is associated with metabolic inefficiency, impaired muscle triglyceride biosynthesis, and accumulation of bioactive lipids and amino acids. Taken together, our data provide a comprehensive overview of how genomic binding of BMAL1 and REV-ERBα is related to temporal changes in gene expression and metabolite fluctuations., Author summary Circadian clocks are known to regulate local and systemic homeostasis by anticipating rhythmic changes in behavior and nutritional state and by compartmentalizing incompatible metabolic pathways within precise temporal and spatial windows. Yet a precise mechanistic understanding of how the circadian clock in skeletal muscle controls homeostasis is just beginning to come to light. Here, we investigated how the muscle clock directs 24-hr metabolic rhythms. We compared genome-wide binding of clock transcription factors brain and muscle ARNT-like protein 1 (BMAL1) and REV-ERBα with 24-hr transcriptional and metabolic effects after their loss of function specifically in muscles. We found that the muscle clock plays a major role anticipating the transition from fasting to feeding. This occurs by direct activation of transcriptional programs promoting lipid storage, insulin sensitivity, and glucose metabolism, with coordinated repression of programs controlling lipid oxidation and protein catabolism. Importantly, these gene expression changes occur in the hours prior to systemic metabolic and hormonal cues that arise upon awakening. As such, we find that the muscle clock tips the scales in favor of glucose metabolism, whereas loss of function of the clock transcription factor BMAL1 is associated with persistent lipid metabolism, protein catabolism, and metabolic inefficiency.
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- 2018
45. Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations
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Giancarlo Iarossi, Enrico Bertini, Andrea Ciolfi, Isabella Moroni, Daniele Ghezzi, Daria Diodato, Costanza Lamperti, Teresa Rizza, Rosalba Carrozzo, Cristina Calderan, Eleonora Lamantea, Stefania Bianchi-Marzoli, Andrea Legati, Michela Di Nottia, Marco Tartaglia, Alessia Nasca, Marcello Niceta, Gianfranco Carrara, Chiara Aiello, Anna Ardissone, Mara Doimo, Leonardo Salviati, Nasca, A, Rizza, T, Doimo, M, Legati, A, Ciolfi, A, Diodato, D, Calderan, C, Carrara, G, Lamantea, E, Aiello, C, Di Nottia, M, Niceta, M, Lamperti, C, Ardissone, A, Bianchi-Marzoli, S, Iarossi, G, Bertini, E, Moroni, I, Tartaglia, M, Salviati, L, Carrozzo, R, and Ghezzi, D
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0301 basic medicine ,Male ,Encephalopathy ,Mitochondrial disorder ,OPA1 ,Optic atrophy ,Recessive trait ,Targeted resequencing ,WES ,Blotting, Western ,Brain Diseases ,Child, Preschool ,Electrophysiology ,GTP Phosphohydrolases ,Humans ,Infant ,Microscopy, Fluorescence ,Mutation ,Optic Atrophy ,Optic Atrophy, Autosomal Dominant ,Tomography, Optical Coherence ,Whole Exome Sequencing ,lcsh:Medicine ,Compound heterozygosity ,GTP Phosphohydrolase ,Missense mutation ,Pharmacology (medical) ,Child ,Tomography ,Exome sequencing ,Genetics (clinical) ,Genetics ,Microscopy ,Blotting ,Brain Disease ,General Medicine ,Hypotonia ,Autosomal Dominant ,medicine.symptom ,Western ,Human ,Ataxia ,Mitochondrial disease ,Biology ,Fluorescence ,Frameshift mutation ,03 medical and health sciences ,Atrophy ,Exome Sequencing ,medicine ,Preschool ,Research ,lcsh:R ,medicine.disease ,eye diseases ,030104 developmental biology ,Optical Coherence - Abstract
Background Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy. Results We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype. The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients’ biological samples, and a clearly fragmented mitochondrial network was observed in patients’ fibroblasts. Conclusions This report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature. Electronic supplementary material The online version of this article (doi:10.1186/s13023-017-0641-1) contains supplementary material, which is available to authorized users.
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- 2017
46. High frequency of mosaic CREBBP deletions in Rubinstein–Taybi syndrome patients and mapping of somatic and germ-line breakpoints
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Angelo Selicorni, Anna Maria Pinto, Maria Luisa Giovannucci-Uzielli, Romano Tenconi, Cristina Gervasini, Francesca Faravelli, Lidia Larizza, Angela Bentivegna, Alice Pessagno, Emanuela Lucci-Cordisco, Paola Castronovo, Federica Mottadelli, Leonardo Salviati, Giovanni Neri, Gervasini, C, Castronovo, P, Bentivegna, A, Mottadelli, F, Faravelli, F, Giovannucci Uzielli, M, Pessagno, A, Lucci Cordisco, E, Pinto, A, Salviati, L, Selicorni, A, Tenconi, R, Neri, G, and Larizza, L
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Adult ,Rubinstein–Taybi syndrome ,MED/03 - GENETICA MEDICA ,DELETIONS RUBINSTEIN-TAYBI SYNDROME ,Biology ,Settore MED/03 - GENETICA MEDICA ,Genome ,Germline ,03 medical and health sciences ,Exon ,medicine ,Genetics ,Humans ,EP300 ,Gene ,Sequence Deletion ,030304 developmental biology ,Rubinstein-Taybi Syndrome ,Breakpoint mapping ,0303 health sciences ,Mosaicism ,030305 genetics & heredity ,Breakpoint ,Infant, Newborn ,Chromosome Mapping ,medicine.disease ,CREB-Binding Protein ,Germ Cells ,CREBBP deletion ,Microsatellite ,Microdeletion ,Female - Abstract
Rubinstein–Taybi syndrome (RSTS) is a rare malformation disorder caused by mutations in the closely related CREBBP and EP300 genes, accounting respectively for up to 60 and 3% of cases. About 10% of CREBBP mutations are whole gene deletions often extending into flanking regions. Using FISH and microsatellite analyses as a first step in the CREBBP mutation screening of 42 Italian RSTS patients, we identified six deletions, three of which were in a mosaic condition that has not been previously reported in RSTS. The use of region-specific BAC clones and small CREBBP probes allowed us to assess the extent of all of the deletions by mapping their endpoints to genomic intervals of 5–10 kb. Four of our five intragenic breakpoints cluster at the 5′ end of CREBBP, where there is a peak of breakpoints underlying rearrangements in RSTS patients and tumors. The search for genomic motifs did not reveal any low-copy repeats (LCRs) or any greater density of repetitive sequences. In contrast, the percentage of interspersed repetitive elements (mainly Alu and LINEs in the CREBBP exon 2 region) is significantly higher than that in the entire gene or the average in the genome, thus suggesting that this characteristic may be involved in the region’s vulnerability to breaking and nonhomologous pairing. The FISH analysis extended to the EP300 genomic region did not reveal any deletions. The clinical presentation was typical in all cases, but more severe in the three patients carrying constitutional deletions, raising a question about the possible underdiagnosis of a few cases of mild RSTS.
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- 2007
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47. Characterization of 14 novel deletions underlying Rubinstein–Taybi syndrome: an update of the CREBBP deletion repertoire
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Margherita Silengo, Vaclava Curtisova, Rita Fischetto, Silvia Spena, Chiara Picinelli, Angelo Selicorni, Leonardo Salviati, Cristina Gervasini, Lidia Larizza, Patrizia Colapietro, Gabriela Stangoni, Cinzia Magnani, Maria Luigia Cavaliere, Maria Piccione, Donatella Milani, Paolo Prontera, L Sorasio, Daniela Rusconi, Gloria Negri, Elisa Biamino, Paolo Gasparini, Giovanni Battista Ferrero, Palma Finelli, Rusconi, Daniela, Negri, Gloria, Colapietro, Patrizia, Picinelli, Chiara, Milani, Donatella, Spena, Silvia, Magnani, Cinzia, Silengo, Margherita Cirillo, Sorasio, Lorena, Curtisova, Vaclava, Cavaliere, Maria Luigia, Prontera, Paolo, Stangoni, Gabriela, Ferrero, Giovanni Battista, Biamino, Elisa, Fischetto, Rita, Piccione, Maria, Gasparini, Paolo, Salviati, Leonardo, Selicorni, Angelo, Finelli, Palma, Larizza, Lidia, Gervasini, Cristina, Rusconi, D., Negri, G., Colapietro, P., Picinelli, C., Milani, D., Spena, S., Magnani, C., Silengo, M., Sorasio, L., Curtisova, V., Cavaliere, M., Prontera, P., Stangoni, G., Ferrero, G., Biamino, E., Fischetto, R., Piccione, M., Gasparini, P., Salviati, L., Selicorni, A., Finelli, P., Larizza, L., and Gervasini, C.
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Adult ,Male ,Adolescent ,Contiguous gene syndrome ,Cohort Studies ,Exon ,Genetic ,medicine ,Genetics ,Humans ,Point Mutation ,CREB-binding protein ,EP300 ,Child ,Preschool ,Genetics (clinical) ,Sequence Deletion ,Rubinstein-Taybi Syndrome ,biology ,medicine.diagnostic_test ,Rubinstein–Taybi syndrome ,Base Sequence ,Point mutation ,Medicine (all) ,Infant, Newborn ,Infant ,Middle Aged ,medicine.disease ,Newborn ,CREB-Binding Protein ,Human genetics ,Child, Preschool ,Female ,biology.protein ,Cohort Studie ,Fluorescence in situ hybridization ,Human - Abstract
Rubinstein–Taybi syndrome (RSTS) is a rare, clinically heterogeneous disorder characterized by cognitive impairment and several multiple congenital anomalies. The syndrome is caused by almost private point mutations in the CREBBP (~55% of cases) and EP300 (~8%) genes. The CREBBP mutational spectrum is variegated and characterized by point mutations (30–50%) and deletions (~10%). The latter are diverse in size and genomic position and remove either the whole CREBBP gene and its flanking regions or only an intragenic portion. Here, we report 14 novel CREBBP deletions ranging from single exons to the whole gene and flanking regions which were identified by applying complementary cytomolecular techniques: fluorescence in situ hybridization, multiplex ligation-dependent probe amplification and array comparative genome hybridization, to a large cohort of RSTS patients. Deletions involving CREBBP account for 23% of our detected CREBBP mutations, making an important contribution to the mutational spectrum. Genotype–phenotype correlations revealed that patients with CREBBP deletions extending beyond this gene did not always have a more severe phenotype than patients harboring CREBBP point mutations, suggesting that neighboring genes play only a limited role in the etiopathogenesis of CREBBP-centerd contiguous gene syndrome. Accordingly, the extent of the deletion is not predictive of the severity of the clinical phenotype.
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- 2015
48. Primary coenzyme Q10 deficiency presenting as fatal neonatal multiorgan failure
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Eva Trevisson, Maurizio Clementi, Leonardo Salviati, Corrado Angelini, Alberto Burlina, Orsetta Zuffardi, Marco Spinazzi, Plácido Navas, Giada Lunardi, Alberto Casarin, María Angeles Hernández, Giovanna Cenacchi, Annalisa Vetro, Ivan Limongelli, Mara Doimo, Maria Andrea Desbats, Lino Chiandetti, Fondazione Cassa di Risparmio di Padova e Rovigo, Fondazione Telethon, Ministero della Salute, Instituto de Salud Carlos III, Junta de Andalucía, Desbats, Ma, Vetro, A, Limongelli, I, Lunardi, G, Casarin, A, Doimo, M, Spinazzi, M, Angelini, C, Cenacchi, G, Burlina, A, Rodriguez Hernandez, Ma, Chiandetti, L, Clementi, M, Trevisson, E, Navas, P, Zuffardi, O, Salviati, L, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
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Ubiquinone ,Gene Expression ,Gastroenterology ,Coenzyme Q10 ,coenzime Q10 deficiency ,COQ2 ,chemistry.chemical_compound ,Consanguinity ,0302 clinical medicine ,Fatal Outcome ,Genetics (clinical) ,Exome sequencing ,Genetics ,0303 health sciences ,Proteinuria ,Muscle Weakness ,Lactic ,Skeletal ,3. Good health ,Mitochondria ,Coenzyme Q10 deficiency ,Muscle ,Acidosis, Lactic ,Female ,medicine.symptom ,Severe lactic acidosis ,Acidosis ,Sequence Analysis ,medicine.medical_specialty ,Ataxia ,Encephalopathy ,Short Report ,Mitochondrial diseases ,Biology ,03 medical and health sciences ,Internal medicine ,Intellectual Disability ,medicine ,Point Mutation ,Hepatic Insufficiency ,Humans ,Renal Aminoacidurias ,Muscle, Skeletal ,030304 developmental biology ,Alkyl and Aryl Transferases ,Genetic heterogeneity ,ataxia ,Infant, Newborn ,Infant ,Sequence Analysis, DNA ,DNA ,medicine.disease ,Newborn ,Mitochondria, Muscle ,chemistry ,030217 neurology & neurosurgery ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Coenzyme Q10 deficiency is a clinically and genetically heterogeneous disorder, with manifestations that may range from fatal neonatal multisystem failure, to adult-onset encephalopathy. We report a patient who presented at birth with severe lactic acidosis, proteinuria, dicarboxylic aciduria, and hepatic insufficiency. She also had dilation of left ventricle on echocardiography. Her neurological condition rapidly worsened and despite aggressive care she died at 23 h of life. Muscle histology displayed lipid accumulation. Electron microscopy showed markedly swollen mitochondria with fragmented cristae. Respiratory-chain enzymatic assays showed a reduction of combined activities of complex I+III and II+III with normal activities of isolated complexes. The defect was confirmed in fibroblasts, where it could be rescued by supplementing the culture medium with 10 μM coenzyme Q10. Coenzyme Q10 levels were reduced (28% of controls) in these cells. We performed exome sequencing and focused the analysis on genes involved in coenzyme Q10 biosynthesis. The patient harbored a homozygous c.545T>G, p.(Met182Arg) alteration in COQ2, which was validated by functional complementation in yeast. In this case the biochemical and morphological features were essential to direct the genetic diagnosis. The parents had another pregnancy after the biochemical diagnosis was established, but before the identification of the genetic defect. Because of the potentially high recurrence risk, and given the importance of early CoQ10 supplementation, we decided to treat with CoQ10 the newborn child pending the results of the biochemical assays. Clinicians should consider a similar management in siblings of patients with CoQ10 deficiency without a genetic diagnosis., This work was supported by grants from Fondazione CARIPARO, Telethon Italy GGP13222 and University of Padova (CPDA123573/12) to LS; Telethon Italy GGP10121 and PRIN 20108WT59Y_003 to OZ; Italian Ministry of Health (GR-2009-1578914) to ET; Spanish FIS grant PI11-00078 and Proyecto Excelencia P08-CTS-03988 to PN.
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- 2015
49. Mutations of cytochrome c identified in patients with thrombocytopenia THC4 affect both apoptosis and cellular bioenergetics
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Annalisa Pastore, Carlos T. Moraes, Cristina Cerqua, Giovanna Russo, Leonardo Salviati, Paola Goffrini, Francesca Meloni, Elena Nicchia, Daniela De Rocco, Anna Savoia, Alessandro Pecci, DE ROCCO, Daniela, Cerqua, C, Goffrini, P, Russo, G, Pastore, A, Meloni, F, Nicchia, Elena, Moraes, Ct, Pecci, A, Salviati, L, Savoia, Anna, De Rocco, Daniela, Cerqua, Cristina, Goffrini, Paola, Russo, Giovanna, Pastore, Annalisa, Meloni, Francesca, Moraes, Carlos T., Pecci, Alessandro, and Salviati, Leonardo
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Male ,Cellular bioenergetics ,Somatic cell ,DNA Mutational Analysis ,Sequence Homology ,Apoptosis ,medicine.disease_cause ,Mice ,Platelet ,Child ,Lung ,Cells, Cultured ,Mutation ,Cultured ,Cytochrome c ,Cytochromes c ,Pedigree ,Amino Acid ,Embryo ,Child, Preschool ,Fibroblast ,Molecular Medicine ,Female ,Human ,Gene isoform ,piastrinopenia ereditaria ,Thrombocytopenia THC4 ,Molecular Sequence Data ,Mutation, Missense ,Settore BIO/11 - Biologia Molecolare ,Saccharomyces cerevisiae ,Biology ,DNA Mutational Analysi ,Oxygen Consumption ,medicine ,citocromo c ,Animals ,Humans ,Amino Acid Sequence ,Preschool ,Gene ,Molecular Biology ,Family Health ,Sequence Homology, Amino Acid ,Base Sequence ,Animal ,Mammalian ,Apoptosi ,Fibroblasts ,Embryo, Mammalian ,Thrombocytopenia ,Molecular biology ,Molecular medicine ,Cellular bioenergetic ,biology.protein ,Cancer research ,Cell ,Missense ,Energy Metabolism - Abstract
Inherited thrombocytopenias are heterogeneous diseases caused by at least 20 genes playing different role in the processes of megakaryopoiesis and platelet production. Some forms, such as thrombocytopenia 4 (THC4), are very rare and not well characterized. THC4 is an autosomal dominant mild thrombocytopenia described in only one large family fromNewZealand and due to amutation (G41S) of the somatic isoform of the cytochrome c (CYCS) gene. We report a novel CYCS mutation (Y48H) in patients from an Italian family. Similar to individuals carrying G41S, they have platelets of normal size and morphology, which are only partially reduced in number, but no prolonged bleeding episodes. In order to determine the pathogenetic consequences of Y48H, we studied the effects of the two CYCS mutations in yeast and mouse cellular models. In both cases, we found reduction ofrespiratory level and increased apoptotic rate, supporting the pathogenetic role of CYCS in thrombocytopenia Inherited thrombocytopenias are heterogeneous diseases caused by at least 20 genes playing different role in the processes of megakaryopoiesis and platelet production. Some forms, such as thrombocytopenia 4 (THC4), are very rare and not well characterized. THC4 is an autosomal dominant mild thrombocytopenia described in only one large family from New Zealand and due to a mutation (G41S) of the somatic isoform of the cytochrome c (CYCS) gene. We report a novel CYCS mutation (Y48H) in patients from an Italian family. Similar to individuals carrying G41S, they have platelets of normal size and morphology, which are only partially reduced in number, but no prolonged bleeding episodes. In order to determine the pathogenetic consequences of Y48H, we studied the effects of the two CYCS mutations in yeast and mouse cellular models. In both cases, we found reduction of respiratory level and increased apoptotic rate, supporting the pathogenetic role of CYCS in thrombocytopenia. © 2013 Elsevier B.V.
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- 2014
50. SEVERE CMT TYPE 2 WITH FATAL ENCEPHALOPATHY ASSOCIATED WITH A NOVEL MFN2 SPLICING MUTATION
- Author
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Tiziana Cavallaro, Maria Giovanna Rossetto, Andrea Vettori, Maria Muglia, Valerio Carelli, Nicolo' Rizzuto, Leonardo Salviati, Maria Luisa Mostacciuolo, Francesca Boaretto, Andrea Martinuzzi, Giovanni Vazza, Alberto Casarin, Boaretto F., Vettori A., Casarin A., Vazza G., Muglia M., Rossetto M.G., Cavallaro T., Rizzuto N., Carelli V., Salviati L., Mostacciuolo M.L., and Martinuzzi A.
- Subjects
Foot drop ,medicine.medical_specialty ,Pathology ,Neurology ,Mammillary body ,RNA Splicing ,Encephalopathy ,GTP Phosphohydrolases ,Mitochondrial Proteins ,Central nervous system disease ,Charcot-Marie-Tooth Disease ,medicine ,Humans ,Family Health ,Brain Diseases ,business.industry ,NEUROPATHY ,Membrane Proteins ,Dysautonomia ,Chorea ,Middle Aged ,medicine.disease ,Introns ,Hyperintensity ,Mutation ,Female ,Neurology (clinical) ,medicine.symptom ,business - Abstract
Mutations in the MFN2 gene, encoding mitofusin2, cause autosomal dominant axonal Charcot-Marie-Tooth type 2 (CMT2A, MIM: 608507).1 MFN2 mutations are also found in CMT2 subjects with optic atrophy2 or cognitive impairment.3 The sibship we studied comprised 3 affected and 3 apparently healthy individuals (figure e-1 on the Neurology ® Web site at www.neurology.org). ### Standard protocol approvals, registrations, and patient consents. The study was approved by the institutional ethics committee. Written informed consent was obtained from all participants in the study. ### Clinical cases and results. For more information, see e-Methods. A 48-year-old woman presented with a 10-year history of progressive leg weakness, foot drop, hypotrophy, areflexia, intact sensation, and cognition. Neurophysiology (table e-1) revealed a severe axonal polyneuropathy. The sural nerve biopsy (figure e-2, A and B) showed reduced fiber densities, loss of large myelinated fibers, and marginal Wallerian degeneration. Teased fibers were thin, with shortened internodes, some ongoing remyelination, and no demyelination. She was wheelchair-bound within 1 year. At age 50, after colectomy, she developed a progressive brainstem syndrome with vomiting, nystagmus, chorea, clouded consciousness, and dysautonomia (hyperthermia, breathing irregularities). MRI showed diffuse T2 hyperintensities in the upper brainstem and periaqueductal gray (figure 1A). Blood and CSF examinations were unremarkable. The patient progressively worsened in spite of aggressive management, including thiamine supplementation, and died 7 days later. Brain pathology revealed symmetric vasculonecrotic lesions in the brainstem and the periaqueductal gray with small hemorrhagic component (figure e-2, C and D). Figure 1 Neuroimaging and molecular data of index case (A) Fluid-attenuated inversion recovery axial (a) and coronal (b) images of case II-7 2 days after onset of the encephalopathic symptoms. Symmetric high signal intensity alterations surround the aqueduct, involve the medial thalami, the mammillary bodies, and the tegmental area. (B) Sequence of the wild-type (WT) and mutated (Mut) MFN2 …
- Published
- 2010
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