399 results on '"Legati, A."'
Search Results
202. Low-dose octreotide is able to cause a maximal inhibition of the glycemic responses to a mixed meal in obese type 2 diabetic patients treated with insulin
- Author
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Giustina, Andrea, primary, Girelli, Angela, additional, Buffoli, M.Grazia, additional, Cimino, Antonion, additional, Legati, Fabio, additional, Valentini, Umberto, additional, and Giustina, Gianni, additional
- Published
- 1991
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203. Effects of methimazole treatment on growth hormone (GH) response to GH-releasing hormone in patients with hyperthyroidism
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Giustina, Andrea, primary, Ferrari, Carlo, additional, Bodini, Corrado, additional, Buffoli, Maria Grazia, additional, Legati, Fabio, additional, Schettino, Maurizio, additional, Zuccato, Fausto, additional, and Wehrenberg, William B., additional
- Published
- 1990
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204. Liver genotoxic activity of an epoxide derivative of the hepatocarcinogenic β-blocker DL-ZAMI 1305
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Presta, M., primary, Chiesa, R., additional, Legati, F., additional, Ginelli, B., additional, Tenca, S., additional, and Ragnotti, G., additional
- Published
- 1990
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205. Central Alpha-2 Adrenergic Function in Patients with Essential Hypertension
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Giustina, A., primary, Doga, M., additional, Bossoni, S., additional, Bodini, C., additional, Legati, F., additional, Pizzocolo, G., additional, and Romanelli, G., additional
- Published
- 1990
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206. Acute effects of cortisone acetate on growth hormone response to growth hormone-releasing hormone in normal adult subjects
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Giustina, Andrea, primary, Doga, Mauro, additional, Bodini, Corrado, additional, Girelli, Angela, additional, Legati, Fabio, additional, Bossoni, Simonetta, additional, and Romanelli, Giuseppe, additional
- Published
- 1990
- Full Text
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207. Chemical structure and genotoxic activity of the hepatocarcinogenic beta-blocker DL-ZAMI 1305
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Presta, M., primary, Legati, F., additional, Chiesa, R., additional, Dell'Era, P., additional, and Ragnotti, G., additional
- Published
- 1990
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208. Book Reviews / Erratum
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T. Torresani, Fernández Martín, P. Rochiccioli, J. Smitz, Akira Sekikawa, B. Sopeña, Hideo Sasaki, P.C. Sizonenko, Diane S. Keeney, Makoto Tominaga, Z. Zadik, B.A.J. Evans, Andrade Olivié, A. Kowarski, Ichiro Komiya, B.D. Brown, E. Flutters, M.T. Tauber, William B. Wehrenberg, Milo Zachmann, J. De Schepper, S. Hachimi-Idrissi, D.J. Hill, R.V.G. García-Mayor, Maurizio Schettino, Johan Auwerx, Anna Rosa Bussi, Gorm Greisen, Takashi Yamada, F. Alexandre, Nobuyuki Takasu, Andrea Giustina, B. Rogé, Hirofumi Fukushima, D.M. Williams, Masao Ota, Pankaja S. Venkataraman, Massimo Licini, J.R. Hawkins, I.A. Hughes, S.A. Chalew, H.R. Davies, I. Dab, J.C. Galofré, Mark A. Brandenburg, Ivar K. Rossavik, Noriko Ohara, Hiromi Ootsuka, Fabio Legati, M.N. Patterson, G.E. Theintz, C. Páramo, J.-E. Toublanc, Afonso Lopes, H. Loeb, Fausto Zuccato, Michael R. Waterman, and J.A. Batch
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Endocrinology ,Endocrinology, Diabetes and Metabolism - Published
- 1992
209. Clinical/Scientific Notes.
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Ardissone, Anna, Piscosquito, Giuseppe, Legati, Andrea, Langella, Tiziana, Lamantea, Eleonora, Garavaglia, Barbara, Salsano, Ettore, Farina, Laura, Moroni, Isabella, Pareyson, Davide, and Ghezzi, Daniele
- Published
- 2015
210. Liver genotoxic activity of the hepatocarcinogen ZAMI 1305 in female Fisher 344 rat
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Ragnotti, G., Presta, Marco, Chiesa, R., Legati, F., Rusnati, Marco, and Maier, J. A. M.
- Published
- 1988
211. Sequential superoxide dismutase administration prevents lipid peroxidation in ischemic/reperfused liver
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Nascimbeni, Riccardo, Legati, F., Salerni, Bruno, and Lojacono, L.
- Published
- 1988
212. Lipid peroxidation, prooxidant/antioxidant disbalance and superoxide dismutase (SOD) protection in the ischemic/reperfused liver
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Nascimbeni, Riccardo, Legati, Salerni, Bruno, Presta, Marco, Lojacono, L., and Ragnotti, G.
- Published
- 1989
213. Critical role of gonadal hormones on the genotoxic activity of the hepatocarcinogen DL-ZAMI 1305
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Marco Presta, Jeanette A.M. Maier, Marina Braga, Giovanna Mazzoleni, Fabio Legati, Roberta Chiesa, Marco Rusnati, Giovanni Ragnotti, and Daniela Calovini
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Male ,Cancer Research ,medicine.medical_specialty ,DNA damage ,Inbred Strains ,Biology ,Cell Transformation ,Propanolamines ,chemistry.chemical_compound ,Sex Factors ,Species Specificity ,Internal medicine ,medicine ,Animals ,Orchiectomy ,Castration ,Gonadal Steroid Hormones ,Neoplastic ,DNA Damage ,Female ,Liver ,Rats ,Inbred F344 ,Testosterone ,Carcinogen ,Rats, Inbred Strains ,Rats, Inbred F344 ,Cell Transformation, Neoplastic ,Endocrinology ,Oncology ,chemistry ,Toxicity ,Phenobarbital ,medicine.drug ,Hormone - Abstract
The DNA damaging capacity of the sex-dependent hepatocarcinogen beta-blocker DL-1-(2-nitro-3-methyl-phenoxy)-3-tert-butylamino-propan-2-ol (DL-ZAMI 1305) was evaluated in different sex hormonal conditions. A single injection of DL-ZAMI 1305 causes DNA damage in the liver of the female but not the male Wistar rat. When the hormonal environment of the female rat is converted to 'male type' by ovariectomy and 1 week of treatment with testosterone, DNA damage by DL-ZAMI 1305 is completely abolished. On the contrary, in male rats orchiectomy coupled to 17 beta-estradiol administration increases the amount of hepatic DNA damage by DL-ZAMI 1305 to values similar to those observed in intact female rats. DL-ZAMI 1305 induces hepatic DNA damage also when administered to female Sprague-Dawley and Fisher 344 female rats. It is uneffective instead on the male rats of these strains. Moreover, in the female Fisher 344 rat phenobarbital pretreatment reduces the DNA damaging capacity of DL-ZAMI 1305. Our data indicate that the genotoxic activity of DL-ZAMI 1305 depends on the sex-hormonal status of the animal and that this is possibly due to a modulation of the microsomal mixed function oxidase system by sex hormones.
- Published
- 1987
214. Inuentario semplice di tutte le materie esattamente descritte che si trouano nel museo Cospiano : non solo le notate nel libro gia stampato e composto dal sig. Lorenzo Legati, ma ancora le aggiunteui in copia dopo la fabrica
- Author
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Lorenzo Legati and Giacomo. Monti
- Published
- 1679
215. Paediatric and adult-onset Parkinsonism in Chediak-Higashi disease: A new family
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Carecchio, M., Salsano, E., Legati, A., Lamperti, C., Corsini, E., Barbara Garavaglia, Pareyson, D., and Ghezzi, D.
216. The relevance of movement disorders gene panels in clinical practice: How many patients are we sorting out?
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Barzaghi, C., Panteghini, C., Carecchio, M., Legati, A., Monti, V., Chiara Reale, Invernizzi, F., and Garavaglia, B.
217. Liver genotoxic activity of the hepatocarcinogen ZAMI 1305 in the female Fisher 344 rat
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Ragnotti, G., Marco PRESTA, Chiesa, R., Legati, F., Rusnati, M., and Maier, J. A. M.
218. Biallelic missense and deep intronic NDUFAF6 variants, unraveled by exome sequencing and mRNA analysis, in patients with Leigh syndrome
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Catania, A., Anna Ardissone, Verrigni, D., Legati, A., Reyes, A., Lamantea, E., Diodato, D., Moroni, I., Bertini, E., Robinson, A., Carrozzo, R., Zeviani, M., and Ghezzi, D.
219. Critical role of gonadal hormones on the genotoxic activity of the hepatocarcinogen DL-ZAMI 1305
- Author
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Ragnotti, Giovanni, primary, Presta, Marco, additional, Maier, Jeanette Anne Marie, additional, Rusnati, Marco, additional, Mazzoleni, Giovanna, additional, Legati, Fabio, additional, Chiesa, Roberta, additional, Braga, Marina, additional, and Calovini, Daniela, additional
- Published
- 1987
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220. Inuentario semplice di tutte le materie esattamente descritte che si trouano nel museo Cospiano : non solo le notate nel libro gia stampato e composto dal sig. Lorenzo Legati, ma ancora le aggiunteui in copia dopo la fabrica
- Author
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Legati, Lorenzo, primary and Monti, Giacomo., additional
- Published
- 1680
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221. Editorial.
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e Igor Legati, Elías Capriles
- Published
- 2013
222. NGS-Based Genetic Analysis in a Cohort of Italian Patients with Suspected Inherited Myopathies and/or HyperCKemia.
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Invernizzi, Federica, Izzo, Rossella, Colangelo, Isabel, Legati, Andrea, Zanetti, Nadia, Garavaglia, Barbara, Lamantea, Eleonora, Peverelli, Lorenzo, Ardissone, Anna, Moroni, Isabella, Maggi, Lorenzo, Bonanno, Silvia, Fiori, Laura, Velardo, Daniele, Magri, Francesca, Comi, Giacomo P., Ronchi, Dario, Ghezzi, Daniele, and Lamperti, Costanza
- Subjects
- *
GENETIC variation , *MUSCLE diseases , *NEUROMUSCULAR diseases , *COHORT analysis , *NUCLEOTIDE sequencing - Abstract
Introduction/Aims HyperCKemia is considered a hallmark of neuromuscular diseases. It can be either isolated or associated with cramps, myalgia, weakness, myoglobinuria, or rhabdomyolysis, suggesting a metabolic myopathy. The aim of this work was to investigate possible genetic causes in order to help diagnose patients with recurrent hyperCKemia or clinical suspicion of inherited metabolic myopathy. Methods A cohort of 139 patients (90 adults and 49 children) was analyzed using a custom panel containing 54 genes associated with hyperCKemia. Results A definite genetic diagnosis was obtained in 15.1% of cases, while candidate variants or variants of uncertain significance were found in a further 39.5%. Similar percentages were obtained in patients with infantile or adult onset, with some different causative genes. RYR1 was the gene most frequently identified, either with single or compound heterozygous variants, while ETFDH variants were the most common cause for recessive cases. In one patient, mRNA analysis allowed identifying a large LPIN1 deletion missed by DNA sequencing, leading to a certain diagnosis. Conclusion These data confirm the high genetic heterogeneity of hyperCKemia and metabolic myopathies. The reduced diagnostic yield suggests the existence of additional genes associated with this condition but also allows speculation that a significant number of cases presenting with hyperCKemia or muscle symptoms are due to extrinsic, not genetic, factors. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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223. Familial Behavioral Variant Frontotemporal Dementia Associated With Astrocyte-Predominant Tauopathy
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Ferrer, Isidre, Legati, Andrea, García-Monco, J. Carlos, Gomez-Beldarrain, Marian, Carmona, Margarita, Blanco, Rosa, Seeley, William W., and Coppola, Giovanni
- Abstract
A familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy is described in 2 sisters born from consanguineous parents. The neuropathologic examination revealed massive accumulation of abnormally hyperphosphorylated, conformational, truncated tau at aspartic acid 421, ubiquitinated and nitrated tau at Tyr29 in cortical astrocyte (including their perivascular foot processes), and Bergmann glia. Smaller amounts of abnormal tau were observed in neurons and rarely in oligodendrocytes. There was decreased expression of glial glutamate transporter in the majority of tau-positive astrocytes. Gel electrophoresis of sarkosyl-insoluble fractions showed 2 bands of 64 and 60 kDa and a doublet of 67 to 70 kDa (which are different from those seen in Alzheimer disease and in typical 4R and 3R tauopathies) together with several bands of lower molecular weight indicative of truncated tau. Analysis of the expression of MAPT isoforms further revealed altered splicing and representation of tau isoforms involving exons 2, 3, and 10. Genetic testing revealed no known mutations in PSEN1, PSEN2, APP, MAPT, GRN, FUS, and TARDBP and no pathologic expansion in C9ORF72. However, a novel rare heterozygous sequence variant(p.Q140H) of uncertain significance was identified in FUS in both siblings.
- Published
- 2015
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224. KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature.
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Ardissone, Anna, Tonduti, Davide, Legati, Andrea, Lamantea, Eleonora, Barone, Rita, Dorboz, Imen, Boespflug-Tanguy, Odile, Nebbia, Gabriella, Maggioni, Marco, Garavaglia, Barbara, Moroni, Isabella, Farina, Laura, Pichiecchio, Anna, Orcesi, Simona, Chiapparini, Luisa, and Ghezzi, Daniele
- Subjects
- *
PROGRESSIVE multifocal leukoencephalopathy , *BRAIN stem , *SPINAL cord , *CALCIFICATION , *TRANSFER RNA , *MAGNETIC resonance imaging - Abstract
Background: KARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed.Results: Herein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects.Conclusions: With our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity. Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay. [ABSTRACT FROM AUTHOR]- Published
- 2018
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225. Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations.
- Author
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Toldo, Irene, Nosadini, Margherita, Boscardin, Chiara, Talenti, Giacomo, Manara, Renzo, Lamantea, Eleonora, Legati, Andrea, Ghezzi, Daniele, Perilongo, Giorgio, and Sartori, Stefano
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LEUKOENCEPHALOPATHIES , *MITOCHONDRIAL pathology , *LACTATES , *BRAIN stem , *NEURORADIOLOGY , *GENETIC mutation - Abstract
A homoallelic missense founder mutation of the iron-sulfur cluster assembly 2 (ISCA2) gene has been recently reported in six cases affected by an autosomal recessive infantile neurodegenerative mitochondrial disorder. We documented a case of a 2-month-old girl presenting with severe hypotonia and nystagmus, who rapidly deteriorated and died at the age of three months. Increased cerebral spinal fluid level of lactate, documented also at the brain spectroscopy, involvement of the cortex, restricted diffusion of white and gray matter abnormalities, sparing of the corpus callosum and extensive involvement of the spinal cord were observed. Her clinical presenting features and course as well as some neuroradiological findings mimicked those of early-onset leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate (LBSL). The analysis of the mitochondrial respiratory chain function showed a reduced activity of complexes II and IV. The girl harboured two heterozygous mutations in the ISCA2 gene. A comprehensive review of the literature and a comparison with the cases of early onset LBSL enabled us to highlight significant differences in the clinical, biochemical and neuroradiological phenotype between the two conditions, which also emerged from the comparison with the other 6 reported cases of ISCA2 gene mutation previously reported. In summary, this represents the second report ever published associating ISCA2 gene mutation with a mitochondrial leukoencephalopathy, with a different genetic mechanism to the previous cases. Molecular analysis of ISCA2 should be included in the genetic panel for the diagnosis of early onset mitochondrial leukoencephalopathies. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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226. LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance.
- Author
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Dallabona, Cristina, Abbink, Truus E. M., Carrozzo, Rosalba, Torraco, Alessandra, Legati, Andrea, van Berkel, Carola G. M., Niceta, Marcello, Langella, Tiziana, Verrigni, Daniela, Rizza, Teresa, Diodato, Daria, Piemonte, Fiorella, Lamantea, Eleonora, Fang, Mingyan, Zhang, Jianguo, Martinelli, Diego, Bevivino, Elsa, Dionisi-Vici, Carlo, Vanderver, Adeline, and Philip, Sunny G.
- Subjects
- *
LEUKOENCEPHALOPATHIES , *MAGNETIC resonance imaging of the brain , *GENETIC mutation , *ALLELES , *MOLECULAR genetics , *MITOCHONDRIAL proteins , *PROGRESSIVE multifocal leukoencephalopathy diagnosis , *AMINO acids , *DOCUMENTATION , *MAGNETIC resonance imaging , *MOLECULAR chaperones , *PROTEINS , *YEAST , *PROGRESSIVE multifocal leukoencephalopathy - Abstract
This study focused on the molecular characterization of patients with leukoencephalopathy associated with a specific biochemical defect of mitochondrial respiratory chain complex III, and explores the impact of a distinct magnetic resonance imaging pattern of leukoencephalopathy to detect biallelic mutations in LYRM7 in patients with biochemically unclassified leukoencephalopathy. 'Targeted resequencing' of a custom panel including genes coding for mitochondrial proteins was performed in patients with complex III deficiency without a molecular genetic diagnosis. Based on brain magnetic resonance imaging findings in these patients, we selected additional patients from a database of unclassified leukoencephalopathies who were scanned for mutations in LYRM7 by Sanger sequencing. Targeted sequencing revealed homozygous mutations in LYRM7, encoding mitochondrial LYR motif-containing protein 7, in four patients from three unrelated families who had a leukoencephalopathy and complex III deficiency. Two subjects harboured previously unreported variants predicted to be damaging, while two siblings carried an already reported pathogenic homozygous missense change. Sanger sequencing performed in the second cohort of patients revealed LYRM7 mutations in three additional patients, who were selected on the basis of the magnetic resonance imaging pattern. All patients had a consistent magnetic resonance imaging pattern of progressive signal abnormalities with multifocal small cavitations in the periventricular and deep cerebral white matter. Early motor development was delayed in half of the patients. All patients but one presented with subacute neurological deterioration in infancy or childhood, preceded by a febrile infection, and most patients had repeated episodes of subacute encephalopathy with motor regression, irritability and stupor or coma resulting in major handicap or death. LYRM7 protein was strongly reduced in available samples from patients; decreased complex III holocomplex was observed in fibroblasts from a patient carrying a splice site variant; functional studies in yeast confirmed the pathogenicity of two novel mutations. Mutations in LYRM7 were previously found in a single patient with a severe form of infantile onset encephalopathy. We provide new molecular, clinical, and neuroimaging data allowing us to characterize more accurately the molecular spectrum of LYRM7 mutations highlighting that a distinct and recognizable magnetic resonance imaging pattern is related to mutations in this gene. Inter- and intrafamilial variability exists and we observed one patient who was asymptomatic by the age of 6 years. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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227. A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques.
- Author
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Moreno, Fermin, Rabinovici, Gil D., Karydas, Anna, Miller, Zachary, Sandy Chan Hsu, Legati, Andrea, Jamie Fong, Schonhaut, Daniel, Esselmann, Hermann, Watson, Christa, Stephens, Melanie L., Kramer, Joel, Wiltfang, Jens, Seeley, William W., Miller, Bruce L., Coppola, Giovanni, and Grinberg, Lea Tenenholz
- Subjects
- *
FRONTOTEMPORAL lobar degeneration , *MOTOR neuron diseases , *AMYLOID plaque - Abstract
Introduction: Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease. Results: We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance. Conclusions: TARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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228. MITOCHONDRIAL DISEASES (Posters): P.186Muscle histopathology in infantile DNM1L-related mitochondrial epileptic encephalopathy is key for clinical diagnosis.
- Author
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Bertini, E., Verrigni, D., Battaglia, D., Torraco, A., Figa Talamanca, L., Carrozzo, R., Diodato, D., D'Amico, A., Papetti, L., Ghezzi, D., Ardissone, A., Lamperti, C., Legati, A., and Goffrini, P.
- Subjects
- *
MITOCHONDRIAL DNA abnormalities , *PEOPLE with epilepsy - Published
- 2018
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229. Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases.
- Author
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Figuccia S, Izzo R, Legati A, Nasca A, Goffrini P, Ghezzi D, and Ceccatelli Berti C
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- Humans, Saccharomyces cerevisiae Proteins genetics, Saccharomyces cerevisiae Proteins metabolism, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, High-Throughput Nucleotide Sequencing, Mutation, Missense, Amino Acyl-tRNA Synthetases genetics, Amino Acyl-tRNA Synthetases metabolism, Mitochondrial Diseases genetics, Saccharomyces cerevisiae genetics, Mitochondria genetics
- Abstract
Aminoacyl-transfer RiboNucleic Acid synthetases (ARSs) are essential enzymes that catalyze the attachment of each amino acid to their cognate tRNAs. Mitochondrial ARSs (mtARSs), which ensure protein synthesis within the mitochondria, are encoded by nuclear genes and imported into the organelle after translation in the cytosol. The extensive use of next generation sequencing (NGS) has resulted in an increasing number of variants in mtARS genes being identified and associated with mitochondrial diseases. The similarities between yeast and human mitochondrial translation machineries make yeast a good model to quickly and efficiently evaluate the effect of variants in mtARS genes. Genetic screening of patients with a clinical suspicion of mitochondrial disorders through a customized gene panel of known disease-genes, including all genes encoding mtARSs, led to the identification of missense variants in WARS2, NARS2 and RARS2. Most of them were classified as Variant of Uncertain Significance. We exploited yeast models to assess the functional consequences of the variants found in these genes encoding mitochondrial tryptophanyl-tRNA, asparaginyl-tRNA, and arginyl-tRNA synthetases, respectively. Mitochondrial phenotypes such as oxidative growth, oxygen consumption rate, Cox2 steady-state level and mitochondrial protein synthesis were analyzed in yeast strains deleted in MSW1, SLM5, and MSR1 (the yeast orthologues of WARS2, NARS2 and RARS2, respectively), and expressing the wild type or the mutant alleles. Pathogenicity was confirmed for most variants, leading to their reclassification as Likely Pathogenic. Moreover, the beneficial effects observed after asparagine and arginine supplementation in the growth medium suggest them as a potential therapeutic approach., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2024
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230. De Novo DNM1L Mutation in a Patient with Encephalopathy, Cardiomyopathy and Fatal Non-Epileptic Paroxysmal Refractory Vomiting.
- Author
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Berti B, Verrigni D, Nasca A, Di Nottia M, Leone D, Torraco A, Rizza T, Bellacchio E, Legati A, Palermo C, Marchet S, Lamperti C, Novelli A, Mercuri EM, Bertini ES, Pane M, Ghezzi D, and Carrozzo R
- Subjects
- Humans, Female, Infant, Fatal Outcome, Brain Diseases genetics, Brain Diseases pathology, GTP Phosphohydrolases genetics, Dynamins genetics, Cardiomyopathies genetics, Mutation genetics
- Abstract
Mitochondrial fission and fusion are vital dynamic processes for mitochondrial quality control and for the maintenance of cellular respiration; they also play an important role in the formation and maintenance of cells with high energy demand including cardiomyocytes and neurons. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family that is responsible for the fission of mitochondria; it is ubiquitous but highly expressed in the developing neonatal heart. De novo heterozygous pathogenic variants in the DNM1L gene have been previously reported to be associated with neonatal or infantile-onset encephalopathy characterized by hypotonia, developmental delay and refractory epilepsy. However, cardiac involvement has been previously reported only in one case. Next-Generation Sequencing (NGS) was used to genetically assess a baby girl characterized by developmental delay with spastic-dystonic, tetraparesis and hypertrophic cardiomyopathy of the left ventricle. Histochemical analysis and spectrophotometric determination of electron transport chain were performed to characterize the muscle biopsy; moreover, the morphology of mitochondria and peroxisomes was evaluated in cultured fibroblasts as well. Herein, we expand the phenotype of DNM1L -related disorder, describing the case of a girl with a heterozygous mutation in DNM1L and affected by progressive infantile encephalopathy, with cardiomyopathy and fatal paroxysmal vomiting correlated with bulbar transitory abnormal T2 hyperintensities and diffusion-weighted imaging (DWI) restriction areas, but without epilepsy. In patients with DNM1L mutations, careful evaluation for cardiac involvement is recommended.
- Published
- 2024
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231. Generation of iPSCs from identical twin, one affected by LHON and one unaffected, both carrying a combination of two mitochondrial variants: m.14484 T>C and m.10680G>A.
- Author
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Peron C, Cavaliere A, Fasano C, Iannielli A, Spagnolo M, Legati A, Nicol Colombo M, Rizzo A, Sciacca FL, Carelli V, Broccoli V, Lamperti C, and Tiranti V
- Subjects
- Humans, Male, Mitochondria metabolism, Mitochondria genetics, Female, Point Mutation, Adult, Optic Atrophy, Hereditary, Leber genetics, Optic Atrophy, Hereditary, Leber pathology, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells cytology, Twins, Monozygotic, DNA, Mitochondrial genetics
- Abstract
Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial illness, causing retinal ganglion cell degeneration and central vision loss. It stems from point mutations in mitochondrial DNA (mtDNA), with key mutations being m.3460G > A, m.11778G > A, and m.14484 T > C. Fibroblasts from identical twins, sharing m.14484 T > C and m.10680G > A variants each with 70 % heteroplasmy, were used to generate iPSC lines. Remarkably, one twin, a LHON patient, displayed symptoms, while the other, a carrier, remained asymptomatic. These iPSCs offer a valuable tool for studying factors influencing disease penetrance and unravelling the role of m.10680G > A, which is still debated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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232. Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY-associated diseases.
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Cavestro C, Morra F, Legati A, D'Amato M, Nasca A, Iuso A, Lubarr N, Morrison JL, Wheeler PG, Serra-Juhé C, Rodríguez-Santiago B, Turón-Viñas E, Prouteau C, Barth M, Hayflick SJ, Ghezzi D, Tiranti V, and Di Meo I
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- Humans, Male, Female, Child, Child, Preschool, Epilepsy genetics, Fibroblasts metabolism, Adolescent, Autism Spectrum Disorder genetics, Adult, Transferases, Phenotype, Transcriptome
- Abstract
Objective: COASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein-associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY-related disorders., Methods: Patients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts., Results: We identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY-related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4'-phosphopantetheinylated proteins were significantly reduced in COASY patients., Interpretation: These results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY-associated diseases., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
- Published
- 2024
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233. A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies.
- Author
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Sala D, Marchet S, Nanetti L, Legati A, Mariotti C, Lamantea E, Ghezzi D, Catania A, and Lamperti C
- Subjects
- Adult, Female, Humans, Male, Middle Aged, DNA, Mitochondrial genetics, Fibroblasts metabolism, Fibroblasts pathology, Italy, Ataxia genetics, Ataxia pathology, Mitochondrial Proton-Translocating ATPases genetics, Mitochondrial Proton-Translocating ATPases metabolism
- Abstract
Background: MT-ATP6 is a mitochondrial gene which encodes for the intramembrane subunit 6 (or A) of the mitochondrial ATP synthase, also known asl complex V, which is involved in the last step of oxidative phosphorylation to produce cellular ATP through aerobic metabolism. Although classically associated with the NARP syndrome, recent evidence highlights an important role of MT-ATP6 pathogenic variants in complicated adult-onset ataxias., Methods: We describe two unrelated patients with adult-onset cerebellar ataxia associated with severe optic atrophy and mild cognitive impairment. Whole mitochondrial DNA sequencing was performed in both patients. We employed patients' primary fibroblasts and cytoplasmic hybrids (cybrids), generated from patients-derived cells, to assess the activity of respiratory chain complexes, oxygen consumption rate (OCR), ATP production and mitochondrial membrane potential., Results: In both patients, we identified the same novel m.8777 T > C variant in MT-ATP6 with variable heteroplasmy level in different tissues. We identifed an additional heteroplasmic novel variant in MT-ATP6, m.8879G > T, in the patients with the most severe phenotype. A significant reduction in complex V activity, OCR and ATP production was observed in cybrid clones homoplasmic for the m.8777 T > C variant, while no functional defect was detected in m.8879G > T homoplasmic clones. In addition, fibroblasts with high heteroplasmic levelsof m.8777 T > C variant showed hyperpolarization of mitochondrial membranes., Conclusions: We describe a novel pathogenic mtDNA variant in MT-ATP6 associated with adult-onset ataxia, reinforcing the value of mtDNA screening within the diagnostic workflow of selected patients with late onset ataxias., (© 2024. The Author(s).)
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- 2024
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234. AFG3L2 Biallelic Mutation: Clinical Heterogeneity in Two Italian Patients.
- Author
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Colucci F, Neri M, Fortunato F, Ferlini A, Carrozzo R, Torraco A, Lamantea E, Legati A, Tecilla G, Pugliatti M, and Sensi M
- Subjects
- Humans, ATPases Associated with Diverse Cellular Activities genetics, Mutation genetics, Italy, ATP-Dependent Proteases genetics, Spinocerebellar Degenerations genetics, Cerebellar Ataxia genetics
- Abstract
AFG3-like matrix AAA peptidase subunit 2 gene (AFG3L2, OMIM * 604,581) biallelic mutations lead to autosomal recessive spastic ataxia-5 SPAX5, OMIM # 614,487), a rare hereditary form of ataxia. The clinical spectrum includes early-onset cerebellar ataxia, spasticity, and progressive myoclonic epilepsy (PME). In Italy, the epidemiology of the disease is probably underestimated. The advent of next generation sequencing (NGS) technologies has speeded up the diagnosis of hereditary diseases and increased the percentage of diagnosis of rare disorders, such as the rare hereditary ataxia groups. Here, we describe two patients from two different villages in the province of Ferrara, who manifested a different clinical ataxia-plus history, although carrying the same biallelic mutation in AFG3L2 (p.Met625Ile) identified through NGS analysis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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235. Variants in ATP5F1B are associated with dominantly inherited dystonia.
- Author
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Nasca A, Mencacci NE, Invernizzi F, Zech M, Keller Sarmiento IJ, Legati A, Frascarelli C, Bustos BI, Romito LM, Krainc D, Winkelmann J, Carecchio M, Nardocci N, Zorzi G, Prokisch H, Lubbe SJ, Garavaglia B, and Ghezzi D
- Subjects
- Humans, Mitochondrial Proton-Translocating ATPases genetics, Mutation, Missense, Pedigree, Proteins genetics, Dystonia genetics, Dystonic Disorders genetics
- Abstract
ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2023
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236. Nanopore long-read next-generation sequencing for detection of mitochondrial DNA large-scale deletions.
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Frascarelli C, Zanetti N, Nasca A, Izzo R, Lamperti C, Lamantea E, Legati A, and Ghezzi D
- Abstract
Primary mitochondrial diseases are progressive genetic disorders affecting multiple organs and characterized by mitochondrial dysfunction. These disorders can be caused by mutations in nuclear genes coding proteins with mitochondrial localization or by genetic defects in the mitochondrial genome (mtDNA). The latter include point pathogenic variants and large-scale deletions/rearrangements. MtDNA molecules with the wild type or a variant sequence can exist together in a single cell, a condition known as mtDNA heteroplasmy. MtDNA single point mutations are typically detected by means of Next-Generation Sequencing (NGS) based on short reads which, however, are limited for the identification of structural mtDNA alterations. Recently, new NGS technologies based on long reads have been released, allowing to obtain sequences of several kilobases in length; this approach is suitable for detection of structural alterations affecting the mitochondrial genome. In the present work we illustrate the optimization of two sequencing protocols based on long-read Oxford Nanopore Technology to detect mtDNA structural alterations. This approach presents strong advantages in the analysis of mtDNA compared to both short-read NGS and traditional techniques, potentially becoming the method of choice for genetic studies on mtDNA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Frascarelli, Zanetti, Nasca, Izzo, Lamperti, Lamantea, Legati and Ghezzi.)
- Published
- 2023
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237. Parkinson's Disease, Parkinsonisms, and Mitochondria: the Role of Nuclear and Mitochondrial DNA.
- Author
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Legati A and Ghezzi D
- Subjects
- Animals, Humans, Mitochondria genetics, Mitochondria metabolism, Mutation, DNA, Mitochondrial genetics, DNA, Mitochondrial metabolism, Parkinson Disease
- Abstract
Purpose of Review: Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in Parkinson's disease (PD) pathophysiology. This paper aims to review the latest literature published, focusing on genetic defects and expression alterations affecting mitochondria-associated genes, in support of their key role in PD pathogenesis., Recent Findings: Thanks to the use of new omics approaches, a growing number of studies are discovering alterations affecting genes with mitochondrial functions in patients with PD and parkinsonisms. These genetic alterations include pathogenic single-nucleotide variants, polymorphisms acting as risk factors, and transcriptome modifications, affecting both nuclear and mitochondrial genes. We will focus on alterations of mitochondria-associated genes described by studies conducted on patients or on animal/cellular models of PD or parkinsonisms. We will comment how these findings can be taken into consideration for improving the diagnostic procedures or for deepening our knowledge on the role of mitochondrial dysfunctions in PD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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238. Mitochondrial DNA Sequencing and Heteroplasmy Quantification by Next Generation Sequencing.
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Legati A, Ghezzi D, and Viscomi C
- Subjects
- Heteroplasmy, Mitochondria genetics, Mutation, Sequence Analysis, DNA methods, DNA, Mitochondrial genetics, High-Throughput Nucleotide Sequencing methods
- Abstract
Over the last 10 years, next generation sequencing (NGS) became the gold standard for both diagnosis and discovery of new disease genes responsible for heterogeneous disorders, such as mitochondrial encephalomyopathies. The application of this technology to mtDNA mutations poses extra challenges compared to other genetic conditions because of the peculiarities of mitochondrial genetics and the requirement for proper NGS data management and analysis. Here, we describe a detailed, clinically relevant protocol to sequence the whole mtDNA and quantify heteroplasmy levels of mtDNA variants, starting from total DNA through the generation of a single PCR amplicon., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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239. Axonal Length Determines Distinct Homeostatic Phenotypes in Human iPSC Derived Motor Neurons on a Bioengineered Platform.
- Author
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Hagemann C, Moreno Gonzalez C, Guetta L, Tyzack G, Chiappini C, Legati A, Patani R, and Serio A
- Subjects
- Axons metabolism, Homeostasis, Humans, Motor Neurons metabolism, Phenotype, Induced Pluripotent Stem Cells metabolism
- Abstract
Stem cell-based experimental platforms for neuroscience can effectively model key mechanistic aspects of human development and disease. However, conventional culture systems often overlook the engineering constraints that cells face in vivo. This is particularly relevant for neurons covering long range connections such as spinal motor neurons (MNs). Their axons extend up to 1m in length and require a complex interplay of mechanisms to maintain cellular homeostasis. However, shorter axons in conventional cultures may not faithfully capture important aspects of their longer counterparts. Here this issue is directly addressed by establishing a bioengineered platform to assemble arrays of human axons ranging from micrometers to centimeters, which allows systematic investigation of the effects of length on human axonas for the first time. This approach reveales a link between length and metabolism in human MNs in vitro, where axons above a "threshold" size induce specific molecular adaptations in cytoskeleton composition, functional properties, local translation, and mitochondrial homeostasis. The findings specifically demonstrate the existence of a length-dependent mechanism that switches homeostatic processes within human MNs. The findings have critical implications for in vitro modeling of several neurodegenerative disorders and reinforce the importance of modeling cell shape and biophysical constraints with fidelity and precision in vitro., (© 2022 Wiley-VCH GmbH.)
- Published
- 2022
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240. Biallelic Variants in ENDOG Associated with Mitochondrial Myopathy and Multiple mtDNA Deletions.
- Author
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Nasca A, Legati A, Meneri M, Ermert ME, Frascarelli C, Zanetti N, Garbellini M, Comi GP, Catania A, Lamperti C, Ronchi D, and Ghezzi D
- Subjects
- DNA, Mitochondrial genetics, DNA, Mitochondrial metabolism, Endonucleases, Humans, Mitochondria metabolism, Endodeoxyribonucleases genetics, Endodeoxyribonucleases metabolism, Mitochondrial Myopathies genetics
- Abstract
Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial DNA (mtDNA) makes it an excellent candidate to participate in mtDNA replication, metabolism and maintenance. Indeed, several roles for ENDOG have been hypothesized, including maturation of RNA primers during mtDNA replication, splicing of polycistronic transcripts and mtDNA repair. To date, ENDOG has been deemed as a determinant of cardiac hypertrophy, but no pathogenic variants or genetically defined patients linked to this gene have been described. Here, we report biallelic ENDOG variants identified by NGS in a patient with progressive external ophthalmoplegia, mitochondrial myopathy and multiple mtDNA deletions in muscle. The absence of the ENDOG protein in the patient's muscle and fibroblasts indicates that the identified variants are pathogenic. The presence of multiple mtDNA deletions supports the role of ENDOG in mtDNA maintenance; moreover, the patient's clinical presentation is very similar to mitochondrial diseases caused by mutations in other genes involved in mtDNA homeostasis. Although the patient's fibroblasts did not present multiple mtDNA deletions or delay in the replication process, interestingly, we detected an accumulation of low-level heteroplasmy mtDNA point mutations compared with age-matched controls. This may indicate a possible role of ENDOG in mtDNA replication or repair. Our report provides evidence of the association of ENDOG variants with mitochondrial myopathy.
- Published
- 2022
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241. A novel MRPS34 gene mutation with combined OXPHOS deficiency in an adult patient with Leigh syndrome.
- Author
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Lenzini L, Carecchio M, Iori E, Legati A, Lamantea E, Avogaro A, and Vitturi N
- Abstract
We report a novel pathogenic variant (c.223G > C; p.Gly75Arg) in the gene encoding the small mitoribosomal subunit protein mS34 in a long-surviving patient with Leigh Syndrome who was genetically diagnosed at age 34 years. The patient presented with delayed motor milestones and a stepwise motor deterioration during life, along with brain MRI alterations involving the subcortical white matter, deep grey nuclei and in particular the internal globi pallidi, that appeared calcified on CT scan. The novel variant is associated with a reduction of mS34 protein levels and of the OXPHOS complex I and IV subunits in peripheral blood mononuclear cells of the case. This study expands the number of variants that, by affecting the stability of the mitoribosome, may cause an OXPHOS deficiency in Leigh Syndrome and reports, for the first time, an unusual long survival in a patient with a homozygous MRPS34 pathogenic variant., (©2021PublishedbyElsevierInc.)
- Published
- 2021
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242. Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia.
- Author
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Yap ZY, Efthymiou S, Seiffert S, Vargas Parra K, Lee S, Nasca A, Maroofian R, Schrauwen I, Pendziwiat M, Jung S, Bhoj E, Striano P, Mankad K, Vona B, Cuddapah S, Wagner A, Alvi JR, Davoudi-Dehaghani E, Fallah MS, Gannavarapu S, Lamperti C, Legati A, Murtaza BN, Nadeem MS, Rehman MU, Saeidi K, Salpietro V, von Spiczak S, Sandoval A, Zeinali S, Zeviani M, Reich A, Jang C, Helbig I, Barakat TS, Ghezzi D, Leal SM, Weber Y, Houlden H, and Yoon WH
- Subjects
- Alleles, Animals, Cells, Cultured, Child, Cohort Studies, DNA Mutational Analysis, Drosophila melanogaster genetics, Family Health, Female, Fibroblasts, Humans, Male, RNA Splicing, Ataxia genetics, Epilepsy genetics, Hearing Loss genetics, Ketoglutarate Dehydrogenase Complex genetics, Mutation, Neurodevelopmental Disorders genetics, Vision Disorders genetics
- Abstract
The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs
∗ 16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans., Competing Interests: Declaration of interests I.H. serves on the Scientific Advisory Board of Biogen. A.R. is an employee of GeneDx. The remaining authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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243. Myopathic mitochondrial DNA depletion syndrome associated with biallelic variants in LIG3.
- Author
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Invernizzi F, Legati A, Nasca A, Lamantea E, Garavaglia B, Gusic M, Kopajtich R, Prokisch H, Zeviani M, Lamperti C, and Ghezzi D
- Subjects
- DNA Ligase ATP, DNA, Mitochondrial genetics, Humans, Poly-ADP-Ribose Binding Proteins, Muscular Diseases
- Published
- 2021
- Full Text
- View/download PDF
244. Editorial: Application of Omics Approaches to the Diagnosis of Genetic Neurological Disorders.
- Author
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Legati A, Giacopuzzi E, Spinazzi M, and Lek M
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2021
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245. Current and New Next-Generation Sequencing Approaches to Study Mitochondrial DNA.
- Author
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Legati A, Zanetti N, Nasca A, Peron C, Lamperti C, Lamantea E, and Ghezzi D
- Subjects
- Genetic Testing methods, Humans, Point Mutation, Sequence Deletion, DNA, Mitochondrial genetics, High-Throughput Nucleotide Sequencing methods
- Abstract
Mitochondria harbor multiple copies of a maternally inherited nonnuclear genome. Point mutations, deletions, or depletion of the mitochondrial DNA (mtDNA) are associated with various human diseases. mtDNA defects are currently studied using Sanger sequencing, Southern blot, and long and quantitative PCR. However, these technologies are expensive and are limited in speed, throughput, and sensitivity. Recently, next-generation sequencing (NGS) has been used to study mtDNA defects; however, its potential applications still need to be fully validated. We analyzed mtDNA from 16 control samples and 33 affected samples, which were previously investigated by traditional techniques. Different NGS approaches were tested, using classic library preparation based on PCR amplifications and an innovative PCR-free protocol, defining their suitability and utility for: i) generating full accurate mtDNA sequence, ii) assessing heteroplasmy for single point mutations with high accuracy, and iii) detecting break positions and heteroplasmy of single large deletions. This study confirmed that PCR-based library preparations are appropriate for the first two points and showed that a new PCR-free method gave the best results for the third aim. This study tested different approaches and describes an innovative PCR-free protocol, suitable for detection and heteroplasmy quantification of mtDNA single large deletions. NGS may become the method of choice for genetic analysis on mtDNA., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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246. Generation of two human iPSC lines, FINCBi002-A and FINCBi003-A, carrying heteroplasmic macrodeletion of mitochondrial DNA causing Pearson's syndrome.
- Author
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Peron C, Mauceri R, Iannielli A, Cavaliere A, Legati A, Rizzo A, Sciacca FL, Broccoli V, and Tiranti V
- Abstract
Pearson marrow pancreas syndrome (PMPS) is a sporadic mitochondrial disease, resulting from the clonal expansion of a mutated mitochondrial DNA (mtDNA) molecule bearing a macro-deletion, and therefore missing essential genetic information. PMPS is characterized by the presence of deleted (Δ) mtDNA that co-exist with the presence of a variable amount of wild-type mtDNA, a condition termed heteroplasmy. All tissues of the affected individual, including the haemopoietic system and the post-mitotic, highly specialized tissues (brain, skeletal muscle, and heart) contain the large-scale mtDNA deletion in variable amount. We generated human induced pluripotent stem cells (hiPSCs) from two PMPS patients, carrying different type of large-scale deletion., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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247. Bi-allelic pathogenic variants in NDUFC2 cause early-onset Leigh syndrome and stalled biogenesis of complex I.
- Author
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Alahmad A, Nasca A, Heidler J, Thompson K, Oláhová M, Legati A, Lamantea E, Meisterknecht J, Spagnolo M, He L, Alameer S, Hakami F, Almehdar A, Ardissone A, Alston CL, McFarland R, Wittig I, Ghezzi D, and Taylor RW
- Subjects
- Alleles, Child, Electron Transport Complex I genetics, Electron Transport Complex I metabolism, Humans, Mitochondrial Proteins genetics, Mutation, Leigh Disease genetics, Mitochondrial Diseases genetics
- Abstract
Leigh syndrome is a progressive neurodegenerative disorder, most commonly observed in paediatric mitochondrial disease, and is often associated with pathogenic variants in complex I structural subunits or assembly factors resulting in isolated respiratory chain complex I deficiency. Clinical heterogeneity has been reported, but key diagnostic findings are developmental regression, elevated lactate and characteristic neuroimaging abnormalities. Here, we describe three affected children from two unrelated families who presented with Leigh syndrome due to homozygous variants (c.346_*7del and c.173A>T p.His58Leu) in NDUFC2, encoding a complex I subunit. Biochemical and functional investigation of subjects' fibroblasts confirmed a severe defect in complex I activity, subunit expression and assembly. Lentiviral transduction of subjects' fibroblasts with wild-type NDUFC2 cDNA increased complex I assembly supporting the association of the identified NDUFC2 variants with mitochondrial pathology. Complexome profiling confirmed a loss of NDUFC2 and defective complex I assembly, revealing aberrant assembly intermediates suggestive of stalled biogenesis of the complex I holoenzyme and indicating a crucial role for NDUFC2 in the assembly of the membrane arm of complex I, particularly the ND2 module., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2020
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248. Response to: "Heterogeneous phenotypic expression of C1QBP variants is attributable to variable heteroplasmy of secondary mtDNA deletions and mtDNA copy number".
- Author
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Lamperti C, Marchet S, Legati A, and Ghezzi D
- Subjects
- Carrier Proteins, DNA Copy Number Variations genetics, Heteroplasmy, Humans, Mitochondrial Proteins, Mutation, DNA, Mitochondrial genetics, Ophthalmoplegia, Chronic Progressive External
- Published
- 2020
- Full Text
- View/download PDF
249. Homozygous mutations in C1QBP as cause of progressive external ophthalmoplegia (PEO) and mitochondrial myopathy with multiple mtDNA deletions.
- Author
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Marchet S, Legati A, Nasca A, Di Meo I, Spagnolo M, Zanetti N, Lamantea E, Catania A, Lamperti C, and Ghezzi D
- Subjects
- DNA, Mitochondrial genetics, Homozygote, Humans, Mutation, Carrier Proteins genetics, Mitochondrial Myopathies genetics, Mitochondrial Proteins genetics, Ophthalmoplegia genetics, Ophthalmoplegia, Chronic Progressive External genetics, Ophthalmoplegia, Chronic Progressive External pathology
- Abstract
Biallelic mutations in the C1QBP gene have been associated with mitochondrial cardiomyopathy and combined respiratory-chain deficiencies, with variable onset (including intrauterine or neonatal forms), phenotypes, and severity. We studied two unrelated adult patients from consanguineous families, presenting with progressive external ophthalmoplegia (PEO), mitochondrial myopathy, and without any heart involvement. Muscle biopsies from both patients showed typical mitochondrial alterations and the presence of multiple mitochondrial DNA deletions, whereas biochemical defects of the respiratory chain were present only in one subject. Using next-generation sequencing approaches, we identified homozygous mutations in C1QBP. Immunoblot analyses in patients' muscle samples revealed a strong reduction in the amount of the C1QBP protein and varied impairment of respiratory chain complexes, correlating with disease severity. Despite the original study indicated C1QBP mutations as causative for mitochondrial cardiomyopathy, our data indicate that mutations in C1QBP have to be considered in subjects with PEO phenotype or primary mitochondrial myopathy and without cardiomyopathy., (© 2020 Wiley Periodicals LLC.)
- Published
- 2020
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250. ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy.
- Author
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Caporali L, Magri S, Legati A, Del Dotto V, Tagliavini F, Balistreri F, Nasca A, La Morgia C, Carbonelli M, Valentino ML, Lamantea E, Baratta S, Schöls L, Schüle R, Barboni P, Cascavilla ML, Maresca A, Capristo M, Ardissone A, Pareyson D, Cammarata G, Melzi L, Zeviani M, Peverelli L, Lamperti C, Marzoli SB, Fang M, Synofzik M, Ghezzi D, Carelli V, and Taroni F
- Subjects
- Adolescent, Adult, Aged, Child, Female, Genetic Testing, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation, Pedigree, Exome Sequencing, Young Adult, ATP-Dependent Proteases genetics, ATPases Associated with Diverse Cellular Activities genetics, GTP Phosphohydrolases genetics, Optic Atrophy genetics, Optic Nerve Diseases genetics
- Abstract
Objective: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed., Methods: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts., Results: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells., Interpretation: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)
- Published
- 2020
- Full Text
- View/download PDF
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