@article{SCOPUS_ID:84884764376,

title = {2mit, an Intronic Gene of Drosophila melanogaster timeless2, Is Involved in Behavioral Plasticity},

author = {Francesca Baggio and Andrea Bozzato and Clara Benna and Emanuela Leonardi and Ottavia Romoli and Moira Cognolato and Silvio C. E. Tosatto and Rodolfo Costa and Federica Sandrelli},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84884764376&origin=inward},

doi = {10.1371/journal.pone.0076351},

year  = {2013},

date = {2013-01-01},

journal = {PLoS ONE},

volume = {8},

number = {9},

abstract = {Background:Intronic genes represent textasciitilde 6% of the total gene complement in Drosophila melanogaster and textasciitilde 85% of them encode for proteins. We recently characterized the D. melanogaster timeless2 (tim2) gene, showing its active involvement in chromosomal stability and light synchronization of the adult circadian clock. The protein coding gene named 2mit maps on the 11th tim2 intron in the opposite transcriptional orientation.Methodology/Principal Findings:Here we report the molecular and functional characterization of 2mit. The 2mit gene is expressed throughout Drosophila development, localizing mainly in the nervous system during embryogenesis and mostly in the mushroom bodies and ellipsoid body of the central complex in the adult brain. In silico analyses revealed that 2mit encodes a putative leucine-Rich Repeat transmembrane receptor with intrinsically disordered regions, harboring several fully conserved functional interaction motifs in the cytosolic side. Using insertional mutations, tissue-specific over-expression, and down-regulation approaches, it was found that 2mit is implicated in adult short-term memory, assessed by a courtship conditioning assay. In D. melanogaster, tim2 and 2mit do not seem to be functionally related. Bioinformatic analyses identified 2MIT orthologs in 21 Drosophilidae, 4 Lepidoptera and in Apis mellifera. In addition, the tim2-2mit host-nested gene organization was shown to be present in A. mellifera and maintained among Drosophila species. Within the Drosophilidae 2mit-hosting tim2 intron, in silico approaches detected a neuronal specific transcriptional binding site which might have contributed to preserve the specific host-nested gene association across Drosophila species. Conclusions/Significance:Taken together, these results indicate that 2mit, a gene mainly expressed in the nervous system, has a role in the behavioral plasticity of the adult Drosophila. The presence of a putative 2mit regulatory enhancer within the 2mit-hosting tim2 intron could be considered an evolutionary constraint potentially involved in maintaining the tim2-2mit host-nested chromosomal architecture during the evolution of Drosophila species. © 2013 Baggio et al.},

note = {Cited by: 7; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84885843727,

title = {A novel SACS mutation results in non-ataxic spastic paraplegia and peripheral neuropathy},

author = {Gregianin and Vazza and Scaramel and Boaretto and Vettori and Leonardi and Tosatto and Manara and Pegoraro and Mostacciuolo},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84885843727&origin=inward},

doi = {10.1111/ene.12220},

year  = {2013},

date = {2013-01-01},

journal = {European Journal of Neurology},

volume = {20},

number = {11},

pages = {1486-1491},

publisher = {Blackwell Publishing Ltdcustomerservices@oxonblackwellpublishing.com},

abstract = {Background and purpose: Mutations in the SACS gene are commonly associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a complex neurodegenerative disorder characterized by progressive degeneration of the cerebellum and spinal cord tracts. The aim of this study was to identify the genetic cause of the disease in an Italian family with spastic paraplegia and peripheral neuropathy. Methods: Affected subjects were subjected to a comprehensive neurological examination including electromyography and brain magnetic resonance imaging. Genetic studies included exclusion of known disease genes, genome-wide linkage analysis using high density single nucleotide polymorphism genotyping and candidate gene sequencing. Results: Molecular analyses revealed a novel missense mutation in the SACS gene (c.11,104A>G) occurring in a homozygous state in patients and absent in 700 Italian control chromosomes. The mutation led to the amino acid substitution p.Thr3702Ala in the sacsin protein, in a possible protein-protein interaction site of UBE3A binding domain. Conclusion: This study broadens the genetic spectrum of SACS mutations and expands the clinical ARSACS phenotype suggesting that the SACS gene can be considered in patients with non-canonical ARSACS clinical presentations. © 2013 EFNS.},

note = {Cited by: 27; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84879800008,

title = {Early-onset epileptic encephalopathy in a girl carrying a truncating mutation of the ARX gene: Rethinking the ARX phenotype in females},

author = {Bettella and Di Rosa and Polli and Leonardi and Tortorella and Sartori and Murgia},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84879800008&origin=inward},

doi = {10.1111/cge.12034},

year  = {2013},

date = {2013-01-01},

journal = {Clinical Genetics},

volume = {84},

number = {1},

pages = {82-85},

abstract = {Severe early-onset epilepsy is due to a number of known causes, although a clear etiology is not identifiable in up to a third of all the cases. Pathogenic sequence variations in the ARX gene have been described almost exclusively in males, whereas heterozygous female relatives, such as mothers, sisters and even grandmothers have been largely reported as asymptomatic or mildly affected. To investigate the pathogenic role of ARX in refractory epilepsy of early onset even in females, we have screened the ARX sequence in a population of 50 female subjects affected with unexplained epileptic encephalopathy with onset in the first year of life. We report the identification of a novel truncating mutation of the coding region of the ARX gene in a girl with a structurally normal brain. Our findings confirm the role of ARX in the pathogenesis of early epilepsy and underline the importance of screening of the ARX gene in both male and female subjects with otherwise unexplained early onset epileptic encephalopathy.© 2012 John Wiley & Sons A/S.},

note = {Cited by: 13},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84876047815,

title = {Fly cryptochrome and the visual system},

author = {Gabriella Mazzotta and Alessandro Rossi and Emanuela Leonardi and Moyra Mason and Cristiano Bertolucci and Laura Caccin and Barbara Spolaore and Alberto J. M. Martin and Matthias Schlichting and Rudi Grebler and Charlotte Helfrich-Förster and Stefano Mammi and Rodolfo Costa and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84876047815&origin=inward},

doi = {10.1073/pnas.1212317110},

year  = {2013},

date = {2013-01-01},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {110},

number = {15},

pages = {6163-6168},

abstract = {Cryptochromes are flavoproteins, structurally and evolutionary related to photolyases, that are involved in the development, magnetoreception, and temporal organization of a variety of organisms. Drosophila CRYPTOCHROME (dCRY) is involved in light synchronization of the master circadian clock, and its C terminus plays an important role in modulating light sensitivity and activity of the protein. The activation of dCRY by light requires a conformational change, but it has been suggested that activation could be mediated also by specific "regulators" that bind the C terminus of the protein. This C-terminal region harbors several protein-protein interaction motifs, likely relevant for signal transduction regulation. Here, we show that some functional linear motifs are evolutionarily conserved in the C terminus of cryptochromes and that class III PDZ-binding sites are selectively maintained in animals. A coimmunoprecipitation assay followed by mass spectrometry analysis revealed that dCRY interacts with Retinal Degeneration A (RDGA) and with Neither Inactivation Nor Afterpotential C (NINAC) proteins. Both proteins belong to a multiprotein complex (the Signalplex) that includes visualsignaling molecules. Using bioinformatic and molecular approaches, dCRY was found to interact with Neither Inactivation Nor Afterpotential C through Inactivation No Afterpotential D (INAD) in a light-dependent manner and that the CRY-Inactivation No Afterpotential D interaction is mediated by specific domains of the two proteins and involves the CRY C terminus. Moreover, an impairment of the visual behavior was observed in fly mutants for dCRY, indicative of a role, direct or indirect, for this photoreceptor in fly vision.},

note = {Cited by: 67; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:84869206683,

title = {Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy},

author = {Luca Bello and Paola Melacini and Raffaele Pezzani and Adele D'Amico and Luisa Piva and Emanuela Leonardi and Annalaura Torella and Gianni Soraru and Arianna Palmieri and Gessica Smaniotto and Bruno F. Gavassini and Andrea Vianello and Vincenzo Nigro and Enrico Bertini and Corrado Angelini and Silvio C. E. Tosatto and Elena Pegoraro},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-84869206683&origin=inward},

doi = {10.1038/ejhg.2012.71},

year  = {2012},

date = {2012-01-01},

journal = {European Journal of Human Genetics},

volume = {20},

number = {12},

pages = {1234-1239},

abstract = {Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan (α-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent α-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function. © 2012 Macmillan Publishers Limited All rights reserved.},

note = {Cited by: 28; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79954525041,

title = {Familial temporal lobe epilepsy with psychic auras associated with a novel LGI1 mutation},

author = {Striano and Busolin and Santulli and Leonardi and Coppola and Vitiello and Rigon and Michelucci and Tosatto and Striano and Nobile},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79954525041&origin=inward},

doi = {10.1212/WNL.0b013e318212ab2e},

year  = {2011},

date = {2011-01-01},

journal = {Neurology},

volume = {76},

number = {13},

pages = {1173-1176},

publisher = {Lippincott Williams and Wilkins},

abstract = {Background: Autosomal dominant lateral temporal epilepsy (ADLTE) is characterized by focal seizures with auditory features or aphasia. Mutations in the LGI1 gene have been reported in up to 50% of ADLTE pedigrees. We report a family with temporal lobe epilepsy characterized by psychic symptoms associated with a novel LGI1 mutation. Methods: All participants were personally interviewed and underwent neurologic examination and video-EEG recordings. LGI1 exons were sequenced by standard methods. Mutant cDNA was transfected into human embryonic kidney 293 cells; both cell lysates and media were analyzed by Western blot. In silico modeling of the Lgi1 protein EPTP domain was carried out using the structure of WD repeat protein and manually refined. Results: Three affected family members were ascertained, 2 of whom had temporal epilepsy with psychic symptoms (déjà vu, fear) but no auditory or aphasic phenomena, while the third had complex partial seizures without any aura. In all patients, we found a novel LGI1 mutation, Arg407Cys, which did not hamper protein secretion in vitro. Mapping of the mutation on a 3-dimensional protein model showed that this mutation does not induce large structural rearrangements but could destabilize interactions of Lgi1 with target proteins. Conclusions: The Arg407Cys is the first mutation with no effect on Lgi1 protein secretion. The uncommon, isolated psychic symptoms associated with it suggests that ADLTE encompasses a wider range of auras of temporal origin than hitherto reported. © 2011 by AAN Enterprises, Inc. All rights reseved.},

note = {Cited by: 44},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79953202854,

title = {A computational model of the LGI1 protein suggests a common binding site for ADAM proteins},

author = {Emanuela Leonardi and Simonetta Andreazza and Stefano Vanin and Giorgia Busolin and Carlo Nobile and Silvio C. E. Tosatto},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79953202854&origin=inward},

doi = {10.1371/journal.pone.0018142},

year  = {2011},

date = {2011-01-01},

journal = {PLoS ONE},

volume = {6},

number = {3},

abstract = {Mutations of human leucine-rich glioma inactivated (LGI1) gene encoding the epitempin protein cause autosomal dominant temporal lateral epilepsy (ADTLE), a rare familial partial epileptic syndrome. The LGI1 gene seems to have a role on the transmission of neuronal messages but the exact molecular mechanism remains unclear. In contrast to other genes involved in epileptic disorders, epitempin shows no homology with known ion channel genes but contains two domains, composed of repeated structural units, known to mediate protein-protein interactions. A three dimensional in silico model of the two epitempin domains was built to predict the structure-function relationship and propose a functional model integrating previous experimental findings. Conserved and electrostatic charged regions of the model surface suggest a possible arrangement between the two domains and identifies a possible ADAM protein binding site in the β-propeller domain and another protein binding site in the leucine-rich repeat domain. The functional model indicates that epitempin could mediate the interaction between proteins localized to different synaptic sides in a static way, by forming a dimer, or in a dynamic way, by binding proteins at different times. The model was also used to predict effects of known disease-causing missense mutations. Most of the variants are predicted to alter protein folding while several other map to functional surface regions. In agreement with experimental evidence, this suggests that non-secreted LGI1 mutants could be retained within the cell by quality control mechanisms or by altering interactions required for the secretion process. © 2011 Leonardi et al.},

note = {Cited by: 35; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:79958845071,

title = {Identification and In Silico Analysis of Novel von Hippel-Lindau (VHL) Gene Variants from a Large Population},

author = {Emanuela Leonardi and Maddalena Martella and Silvio C. E. Tosatto and Alessandra Murgia},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-79958845071&origin=inward},

doi = {10.1111/j.1469-1809.2011.00647.x},

year  = {2011},

date = {2011-01-01},

journal = {Annals of Human Genetics},

volume = {75},

number = {4},

pages = {483-496},

abstract = {Mutational inactivation of the VHL gene is the cause of von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary cancer syndrome predisposing to haemangioblastomas, pheochromocytomas and clear-cell renal carcinomas. The gene product (pVHL) functions as an adapter in cellular processes including cell growth and apoptosis. VHL mutation analysis was carried out in 426 unrelated subjects with phenotypes ranging from VHL syndrome, to isolated VHL-related tumours that could represent the first manifestation of the disease. A total of 111 individuals were found to carry alterations, with large deletions representing 40% of the variants. Eighteen of the 95 detected variants were novel, seemingly disease-causing mutations; their pathogenic role has been evaluated in silico for effects on protein folding and interactions. Putative regions of interaction between pVHL and proteins involved in common pathways have been identified, assessing possible implications for the presence of mutations in these regions. All new variants predicted to truncate or cause complete pVHL loss of structure were associated with phenotypes consistent with VHL type 1. Seven of the new amino acid substitutions are disease-causing mutations, one is a neutral variant, whereas the results for two remain ambiguous. Our combined molecular and in silico approach for the evaluation of putative disease-causing mutations contributes to the interpretation of the potential pathogenicity of these novel variants. © 2011 The Authors Annals of Human Genetics © 2011 Blackwell Publishing Ltd/University College London.},

note = {Cited by: 21},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:77950937930,

title = {A novel WT1 gene mutation in a three-generation family with progressive isolated focal segmental glomerulosclerosis},

author = {Elisa Benetti and Gianluca Caridi and Cristina Malaventura and Monica Dagnino and Emanuela Leonardi and Lina Artifoni and Gian Marco Ghiggeri and Silvio C. E. Tosatto and Luisa Murer},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-77950937930&origin=inward},

doi = {10.2215/CJN.05670809},

year  = {2010},

date = {2010-01-01},

journal = {Clinical Journal of the American Society of Nephrology},

volume = {5},

number = {4},

pages = {698-702},

abstract = {Background and objectives: Wilms tumor-suppressor gene-1 (WT1) plays a key role in kidney development and function. WT1 mutations usually occur in exons 8 and 9 and are associated with Denys-Drash, or in intron 9 and are associated with Frasier syndrome. However, overlapping clinical and molecular features have been reported. Few familial cases have been described, with intrafamilial variability. Sporadic cases of WT1 mutations in isolated diffuse mesangial sclerosis or focal segmental glomerulosclerosis have also been reported. Design, setting, participants, & measurements: Molecular analysis of WT1 exons 8 and 9 was carried out in five members on three generations of a family with late-onset isolated proteinuria. The effect of the detected amino acid substitution on WT1 protein's structure was studied by bioinformatics tools. Results: Three family members reached end-stage renal disease in full adulthood. None had genital abnormalities or Wilms tumor. Histologic analysis in two subjects revealed focal segmental glomerulosclerosis. The novel sequence variant c. 1208G > A in WT1 exon 9 was identified in all of the affected members of the family. Conclusions: The lack of Wilms tumor or other related phenotypes suggests the expansion of WT1 gene analysis in patients with focal segmental glomerulosclerosis, regardless of age or presence of typical Denys-Drash or Frasier syndrome clinical features. Structural analysis of the mutated protein revealed that the mutation hampers zinc finger-DNA interactions, impairing target gene transcription. This finding opens up new issues about WT1 function in the maintenance of the complex gene network that regulates normal podocyte function. copyright © 2010 by the American Society of Nephrology.},

note = {Cited by: 33; Open Access},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{SCOPUS_ID:77954780222,

title = {Spectrum and frequency of SLC26A4 mutations among czech patients with early hearing loss with and without enlarged vestibular aqueduct (EVA)},

author = {Radka Pourová and Petr Janoušek and Michal Jurovčík and Marcela Dvořáková and Marcela Malíková and Dagmar Rašková and Olga Bendová and Emanuela Leonardi and Alessandra Murgia and Zdenek Kabelka and Jaromír Astl and Pavel Seeman},

url = {https://www.scopus.com/record/display.uri?eid=2-s2.0-77954780222&origin=inward},

doi = {10.1111/j.1469-1809.2010.00581.x},

year  = {2010},

date = {2010-01-01},

journal = {Annals of Human Genetics},

volume = {74},

number = {4},

pages = {299-307},

abstract = {Summary: Mutations in SLC26A4 cause Pendred syndrome (PS) - hearing loss with goitre - or DFNB4 - non-syndromic hearing loss (NSHL) with inner ear abnormalities such as Enlarged Vestibular Aqueduct (EVA) or Mondini Dysplasia (MD). We tested 303 unrelated Czech patients with early hearing loss (298 with NSHL and 5 with PS), all GJB2-negative, for SLC26A4 mutations and evaluated their clinical and radiological phenotype. Among 115 available HRCT/MRI scans we detected three MD (2.6%), three Mondini-like affections (2.6%), 16 EVA (13 bilateral - 19.2% and 15.6% respectively) and 61 EVA/MD-negative scans (73.4%). We found mutation(s) in 26 patients (8.6%) and biallelic mutations in eight patients (2.7%) out of 303 tested. In 18 of 26 (69%) patients, no second mutation could be detected even using MLPA. The spectrum of SLC26A4 mutations in Czech patients is broad without any prevalent mutation. We detected 21 different mutations (four novel). The most frequent mutations were p.Val138Phe and p.Leu445Trp (18% and 8.9% of pathogenic alleles respectively). Among 13 patients with bilateral EVA, six patients (50%) carry biallelic mutations. In EVA -negative patients no biallelic mutations were found but 4.9% had monoallelic mutations. SLC26A4 mutations are present mostly in patients with EVA/MD and/or progressive HL and those with affected siblings. © 2010 The Authors Journal compilation.},

note = {Cited by: 35},

keywords = {},

pubstate = {published},

tppubtype = {article}

}