Eva Trevisson
@sdb.unipd.it
Department of Women's and Children's Health
University of Padova
My research has focused on the study of the genetic bases and the pathogenesis of different genetic diseases, including inherited metabolic disorders (isolated cytochrome c oxidase defect, primary coenzyme Q deficiency) and urea cycle defects.
I set up different systems to validate pathogenic mutations and to establish genotype-phenotype correlations, using different approaches in both yeast and mammalian cells. To unravel the function of different genes involved in mitochondrial respiratory chain, I also employ multicellular organisms, including C.elegans and Zebrafish.
I am now involved in cancer genetics research, particularly on the study of the mechanisms driving pediatric cancers associated with a genetic predisposition. I am employing the same organisms to model germline mutations in oncosuppressors/oncogenes identified in rare tumor predisposing syndromes in order to deeply analyze cancerogenesis and to set up simple models for drug screening.
Concerning Clinical Genetics, my
EDUCATION
PhD program in Developmental Medicine and Health Planning Sciences, Department of Paediatrics, University of Padova. Research Line: rare diseases. Mention of Doctor Europaeus
Medical School, University of Padova, degree magna cum laude
RESEARCH, TEACHING, or OTHER INTERESTS
Genetics, Genetics (clinical), Molecular Medicine, Molecular Biology
Scopus Publications
Scopus Publications
Tito Brambullo, Alberto De Lazzari, Arianna Franchi, Eva Trevisson, Maria Luisa Garau, Federico Scarmozzino, Vincenzo Vindigni, and Franco Bassetto
MDPI AG
Aim of the report: Brooke–Spiegler syndrome (BSS) is a rare autosomal dominant disease characterized by the growth of cylindromas, spiradenomas, trichoepitheliomas, or their combination. These neoplasms usually begin in the second decade and progressively increase in number and size over the years. Diagnosis necessitates consideration of family history, clinical examination, histological findings, and genetic analysis. The aim of this paper is to explore the clinical overlap between Brooke–Spiegler syndrome (BSS) and neurofibromatosis type 1 (NF1). We aim to highlight the challenges associated with their differential diagnosis and emphasize the lack of standardized diagnostic criteria and treatment approaches. Case presentation: Hereby, we introduce the case of a 28-year-old male referred for suspicion of neurofibromatosis type 1 (NF1) who initially declined the recommended surgical excision for a scalp mass. After four years, he returned with larger masses of the scalp, and underwent excision of multiple masses, revealing cylindromas, spiradenomas, and spiradenocylindromas. Family history reported similar tumors in his father, who was also diagnosed with NF1 for the presence of multiple subcutaneous lesions on the scalp. Clinical overlap led to a genetic consultation, but testing for CYLD mutations yielded no significant variations. Despite this, the strong family history and consistent findings led to a revised diagnosis of Brooke–Spiegler syndrome, correcting the initial misdiagnosis of NF1 syndrome. Conclusions: Thanks to the evolving landscape of BSS research over the past two decades, its molecular underpinnings, clinical presentation, and histopathological features are now clearer. However, a thorough family history assessment is mandatory when BSS is suspected. It is our belief that a multidisciplinary approach and cooperation between specialists are essential when dealing with BSS. By sharing this case, we hope to underscore the importance of considering BSS as a differential diagnosis, especially in cases with atypical presentations or overlapping features with other syndromes like NF1.
Linda Rossini, Claudia Maria Bonardi, Silvia Bresolin, Eva Trevisson, and Antonio Marzollo
Springer Science and Business Media LLC
Ludovic Pelosi, Laura Morbiato, Arthur Burgardt, Fiorella Tonello, Abigail K. Bartlett, Rachel M. Guerra, Katayoun Kazemzadeh Ferizhendi, Maria Andrea Desbats, Bérengère Rascalou, Marco Marchi,et al.
Elsevier BV
Cristina Calderan, Ugo Sorrentino, Luca Persano, Eva Trevisson, Geppo Sartori, Leonardo Salviati, and Maria Andrea Desbats
Springer Science and Business Media LLC
Elisabetta Pilotto, Eva Trevisson, Elisabetta Beatrice Nacci, Evelyn Longhin, Francesca Guidolin, and Edoardo Midena
SAGE Publications
Background: Oguchi disease is a rare autosomal recessive retinal dystrophy, characterized by congenital stationary blindness and caused by pathogenic variants in SAG and GRK1 genes. The present study aimed to report an Italian patient affected by Oguchi disease, evaluated by means of a multimodal retinal imaging study and harboring two novel heterozygous pathogenic variants in the SAG gene. Materials and methods: A 60-year-old female complaining congenital stationary night blindness was investigated through fundus photograph, optical coherence tomography (OCT), electroretinography (ERG), and genetic testing. Results: Fundus examination showed a golden-grayish fundus aspect. The rod response of the scotopic ERG was undetectable and mixed rod-cone response was electronegative. Fundus photographs obtained in light and in prolonged dark-adapted conditions allowed to detect the Mizuo-Nakamura phenomenon. Light condition OCT over the abnormal retinal regions showed high-intensity areas in the outer photoreceptor segment layer, that reduced with prolonged dark adaption. Genetic testing identified two rare heterozygous sequence variants in the SAG gene: NM_000541.5:c.807delA p.(Glu270Lysfs*9) and NM_000541.5:c.1047-1G>C confirming the diagnosis of Oguchi disease. Conclusions: We identified the first Italian compound heterozygous patient harboring two novel alterations in the SAG gene (a frameshift deletion and a splicing variant). The involvement of the SAG gene in Oguchi disease is a common finding in Japanese population, but rarely identified in Caucasians. Clinical suspicion should prompt the molecular analysis of genes associated with this condition.
Scott R. Plotkin, Ludwine Messiaen, Eric Legius, Patrice Pancza, Robert A. Avery, Jaishri O. Blakeley, Dusica Babovic-Vuksanovic, Rosalie Ferner, Michael J. Fisher, Jan M. Friedman,et al.
Elsevier BV
Lisa Gambarotto, Samuele Metti, Martina Chrisam, Cristina Cerqua, Patrizia Sabatelli, Andrea Armani, Carlo Zanon, Marianna Spizzotin, Silvia Castagnaro, Flavie Strappazzon,et al.
Wiley
AbstractBackgroundMaintaining healthy mitochondria is mandatory for muscle viability and function. An essential surveillance mechanism targeting defective and harmful mitochondria to degradation is the selective form of autophagy called mitophagy. Ambra1 is a multifaceted protein with well‐known autophagic and mitophagic functions. However, the study of its role in adult tissues has been extremely limited due to the embryonic lethality caused by full‐body Ambra1 deficiency.MethodsTo establish the role of Ambra1 as a positive regulator of mitophagy, we exploited in vivo overexpression of a mitochondria‐targeted form of Ambra1 in skeletal muscle. To dissect the consequence of Ambra1 inactivation in skeletal muscle, we generated muscle‐specific Ambra1 knockout (Ambra1fl/fl:Mlc1f‐Cre) mice. Mitochondria‐enriched fractions were obtained from muscles of fed and starved animals to investigate the dynamics of the mitophagic flux.ResultsOur data show that Ambra1 has a critical role in the mitophagic flux of adult murine skeletal muscle and that its genetic inactivation leads to mitochondria alterations and myofibre remodelling. Ambra1 overexpression in wild‐type muscles is sufficient to enhance mitochondria clearance through the autophagy‐lysosome system. Consistently with this, Ambra1‐deficient muscles display an abnormal accumulation of the mitochondrial marker TOMM20 by +76% (n = 6–7; P < 0.05), a higher presence of myofibres with swollen mitochondria by +173% (n = 4; P < 0.05), and an alteration in the maintenance of the mitochondrial membrane potential and a 34% reduction in the mitochondrial respiratory complex I activity (n = 4; P < 0.05). Lack of Ambra1 in skeletal muscle leads to impaired mitophagic flux, without affecting the bulk autophagic process. This is due to a significantly decreased recruitment of DRP1 (n = 6–7 mice; P < 0.01) and Parkin (n = 6–7 mice; P < 0.05) to the mitochondrial compartment, when compared with controls. Ambra1‐deficient muscles also show a marked dysregulation of the endolysosome compartment, as the incidence of myofibres with lysosomal accumulation is 20 times higher than wild‐type muscles (n = 4; P < 0.05). Histologically, Ambra1‐deficient muscles of both 3‐ and 6‐month‐old animals display a significant decrease of myofibre cross‐sectional area and a 52% reduction in oxidative fibres (n = 6–7; P < 0.05), thus highlighting a role for Ambra1 in the proper structure and activity of skeletal muscle.ConclusionsOur study indicates that Ambra1 is critical for skeletal muscle mitophagy and for the proper maintenance of functional mitochondria.
Eleonora Cosmo, Luisa Frizziero, Giacomo Miglionico, Chiara Sofia De Biasi, Marisa Bruno, Eva Trevisson, Ilaria Gabbiato, Giulia Midena, and Raffaele Parrozzani
MDPI AG
The purpose of this study was to assess the long-term natural history of choroidal abnormalities (CAs) in a large pediatric neurofibromatosis type 1 (NF1) population, quantifying their progression in number and dimensions. Pediatric patients (<16 years old) affected by NF1 with a minimum follow-up of 3 years with at least one CA in one eye were consecutively recruited. Near-infrared (NIR) imaging was performed to identify CAs, which were quantified in number and size. The CAs area and perimeter were normalized for the optic disc dimensions to avoid possible bias related to the growing process of the eye. Ninety-nine eyes of 53 patients were evaluated. The CAs number, area and perimeter significantly increased during follow-up (p < 0.0001 for each parameter). The patient age at baseline was inversely correlated with the CAs number over time (coefficient = −0.1313, p = 0.0068), while no correlation was found between the patient age and CAs progression in size. In conclusion, we provide evidence that, in NF1 pediatric patients, CAs change over time, increasing both in number and dimensions, independently from the physiological growth of the eye. While the increase of the CAs number occurs particularly at an earlier age, the increase in the CAs dimensions is a slow process that remains constant during childhood.
Denis Vecellio Reane, Cristina Cerqua, Sabrina Sacconi, Leonardo Salviati, Eva Trevisson, and Anna Raffaello
MDPI AG
Alternative splicing, the process by which exons within a pre-mRNA transcript are differentially joined or skipped, is crucial in skeletal muscle since it is required both during myogenesis and in post-natal life to reprogram the transcripts of contractile proteins, metabolic enzymes, and transcription factors in functionally distinct muscle fiber types. The importance of such events is underlined by the numerosity of pathological conditions caused by alternative splicing aberrations. Importantly, many skeletal muscle Ca2+ homeostasis genes are also regulated by alternative splicing mechanisms, among which is the Mitochondrial Ca2+ Uniporter (MCU) genuine activator MICU1 which regulates MCU opening upon cell stimulation. We have previously shown that murine skeletal muscle MICU1 is subjected to alternative splicing, thereby generating a splice variant—which was named MICU1.1—that confers unique properties to the mitochondrial Ca2+ uptake and ensuring sufficient ATP production for muscle contraction. Here we extended the analysis of MICU1 alternative splicing to human tissues, finding two additional splicing variants that were characterized by their ability to regulate mitochondrial Ca2+ uptake. Furthermore, we found that MICU1 alternative splicing is induced during myogenesis by the splicing factor RBFOX2. These results highlight the complexity of the alternative splicing mechanisms in skeletal muscle and the regulation of mitochondrial Ca2+ among tissues.
Ugo Sorrentino, Chiara Piccolo, Chiara Rigon, Valeria Brasson, Eva Trevisson, Francesca Boaretto, Alessandro Martini, and Matteo Cassina
MDPI AG
Since the early 2000s, an ever-increasing subset of missense pathogenic variants in the ACTG1 gene has been associated with an autosomal-dominant, progressive, typically post-lingual non-syndromic hearing loss (NSHL) condition designed as DFNA20/26. ACTG1 gene encodes gamma actin, the predominant actin protein in the cytoskeleton of auditory hair cells; its normal expression and function are essential for the stereocilia maintenance. Different gain-of-function pathogenic variants of ACTG1 have been associated with two major phenotypes: DFNA20/26 and Baraitser–Winter syndrome, a multiple congenital anomaly disorder. Here, we report a novel ACTG1 variant [c.625G>A (p. Val209Met)] in an adult patient with moderate-severe NSHL characterized by a downsloping audiogram. The patient, who had a clinical history of slowly progressive NSHL and tinnitus, was referred to our laboratory for the analysis of a large panel of NSHL-associated genes by next generation sequencing. An extensive review of previously reported ACTG1 variants and their associated phenotypes was also performed.
Ugo Sorrentino, Silvia Bellonzi, Chiara Mozzato, Valeria Brasson, Irene Toldo, Raffaele Parrozzani, Maurizio Clementi, Matteo Cassina, and Eva Trevisson
MDPI AG
An increased lifetime risk of epilepsy has been reported in neurofibromatosis type 1 (NF1) patients, ranging between 4% and 14%. To further analyze the correlation between NF1 and epilepsy, we retrospectively reviewed the epidemiologic, clinical, radiological, and molecular data of 784 unselected patients diagnosed with NF1 and referred to the neurofibromatosis outpatient clinics at the University Hospital of Padua. A crude prevalence of epilepsy of 4.7% was observed. In about 70% of cases, seizures arose in the context of neuroradiological findings, with the main predisposing factors being cerebral vasculopathies and hydrocephalus. In the absence of structural abnormalities, the prevalence of epilepsy was found to be 1.27%, which is approximately equal to the total prevalence in the general population. NF1 patients with seizures exhibit a higher incidence of intellectual disability and/or developmental delay, as well as of isolated learning disabilities. The comparison of causative NF1 mutations between the two groups did not reveal a specific genotype–phenotype correlation. Our data refine the current knowledge on epileptological manifestations in NF1 patients, arguing against the hypothesis that specific mechanisms, inherent to neurofibromin cellular function, might determine an increased risk of epilepsy in this condition.
Diana Corallo, Carlo Zanon, Marcella Pantile, Gian Paolo Tonini, Angelica Zin, Samuela Francescato, Bartolomeo Rossi, Eva Trevisson, Claudia Pinato, Ezequiel Monferrer,et al.
MDPI AG
Neuroblastoma (NB) is the most common extra-cranial malignancy in preschool children. To portray the genetic landscape of an overly aggressive NB leading to a rapid clinical progression of the disease, tumor DNA collected pre- and post-treatment has been analyzed. Array comparative genomic hybridization (aCGH), whole-exome sequencing (WES), and pharmacogenetics approaches, respectively, have identified relevant copy number alterations (CNAs), single nucleotide variants (SNVs), and polymorphisms (SNPs) that were then combined into an integrated analysis. Spontaneously formed 3D tumoroids obtained from the recurrent mass have also been characterized. The results prove the power of combining CNAs, SNVs, and SNPs analyses to assess clonal evolution during the disease progression by evidencing multiple clones at disease onset and dynamic genomic alterations during therapy administration. The proposed molecular and cytogenetic integrated analysis empowers the disease follow-up and the prediction of tumor recurrence.
Eric Legius, Ludwine Messiaen, Pierre Wolkenstein, Patrice Pancza, Robert A. Avery, Yemima Berman, Jaishri Blakeley, Dusica Babovic-Vuksanovic, Karin Soares Cunha, Rosalie Ferner,et al.
Elsevier BV
Valeria Morbidoni, Emanuele Agolini, Kevin C Slep, Luca Pannone, Daniela Zuccarello, Matteo Cassina, Enrico Grosso, Giorgia Gai, Leonardo Salviati, Bruno Dallapiccola,et al.
BMJ
BackgroundDysfunction in non-motile cilia is associated with a broad spectrum of developmental disorders characterised by clinical heterogeneity. While over 100 genes have been associated with primary ciliopathies, with wide phenotypic overlap, some patients still lack a molecular diagnosis.ObjectiveTo investigate and functionally characterise the molecular cause of a malformation disorder observed in two sibling fetuses characterised by microphthalmia, cleft lip and palate, and brain anomalies.MethodsA trio-based whole exome sequencing (WES) strategy was used to identify candidate variants in the TOGARAM1 gene. In silico, in vitro and in vivo (Caenorhabditis elegans) studies were carried out to explore the impact of mutations on protein structure and function, and relevant biological processes.ResultsTOGARAM1 encodes a member of the Crescerin1 family of proteins regulating microtubule dynamics. Its orthologue in C. elegans, che-12, is expressed in a subset of sensory neurons and localises in the dendritic cilium where it is required for chemosensation. Nematode lines harbouring the corresponding missense variant in TOGARAM1 were generated by CRISPR/Cas9 technology. Although chemotaxis ability on a NaCl gradient was not affected, che-12 point mutants displayed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. Finally, in vitro analysis of microtubule polymerisation in the presence of wild-type or mutant TOG2 domain revealed a faster polymerisation associated with the mutant protein, suggesting aberrant tubulin binding.ConclusionsOur data are in favour of a causative role of TOGARAM1 variants in the pathogenesis of this novel disorder, connecting this gene with primary ciliopathy.
Cristina Cerqua, Lisa Buson, and Eva Trevisson
Springer International Publishing
G. Brea-Calvo, María Alcázar-Fabra, E. Trevisson and Plácido Navas
Raffaele Parrozzani, Luisa Frizziero, Sara Trainiti, Andrea Calciati, Davide Londei, Giacomo Miglionico, Eva Trevisson, Giulia Midena, Elisabetta Pilotto, and Edoardo Midena
Ovid Technologies (Wolters Kluwer Health)
Purpose: To analyze and classify neurofibromatosis Type 1 (NF1)-related retinal vascular abnormalities (RVAs), their natural history and correlation with disease severity, in a large cohort of patients. Methods: This was an observational longitudinal study with prospective enrollment. Four hundred and seventy-three patients affected by NF1 and 150 age-matched healthy subjects were consecutively enrolled. Retinal vascular abnormalities were detected by means of near-infrared reflectance and studied by optical coherence tomography angiography. The superficial vascular plexus and the deep vascular complex (DVC) were quantitatively and qualitatively analyzed. Results: We identified RVAs in 82 of 473 (17%) NF1 patients, but in none of the 150 healthy subjects. A comparison revealed that NF1 patients with RVAs showed a higher number of NF1 diagnostic criteria (4.3 ± 1.5 vs. 3.9 ±1.5, respectively; P = 0.02) than patients without RVAs. Three different RVA types were identified on optical coherence tomography angiography: macrovascular angiomatosis of the sole superficial vascular plexus; macrovascular angiomatosis of the superficial vascular plexus combined with microvascular angiomatosis of the deep vascular complex; and combined macrovascular angiomatosis of both superficial vascular plexus and deep vascular complex. The prospective analysis of optical coherence tomography angiography images showed no significant longitudinal evolution of RVAs (mean follow-up: 3.7 ± 2.8 years). A single patient developed a de novo single RVA, and two RVAs showed detectable changes during follow-up. Conclusion: In NF1 patients, RVAs are a characteristic sign that correlates with a more severe systemic disease expression, usually remaining stable during time. Optical coherence tomography angiography allows for the identification of different RVAs subtypes.
María Alcázar-Fabra, Francisco Rodríguez-Sánchez, Eva Trevisson, and Gloria Brea-Calvo
Elsevier BV
Valeria Morbidoni, Elisa Baschiera, Monica Forzan, Valentina Fumini, Dario Seif Ali, Gianpietro Giorgi, Lisa Buson, Maria Andrea Desbats, Matteo Cassina, Maurizio Clementi,et al.
MDPI AG
Neurofibromatosis type 1 (NF1) is caused by heterozygous loss of function mutations in the NF1 gene. Although patients are diagnosed according to clinical criteria and few genotype-phenotype correlations are known, molecular analysis remains important. NF1 displays allelic heterogeneity, with a high proportion of variants affecting splicing, including deep intronic alleles and changes outside the canonical splice sites, making validation problematic. Next Generation Sequencing (NGS) technologies integrated with multiplex ligation-dependent probe amplification (MLPA) have largely overcome RNA-based techniques but do not detect splicing defects. A rapid minigene-based system was set up to test the effects of NF1 variants on splicing. We investigated 29 intronic and exonic NF1 variants identified in patients during the diagnostic process. The minigene assay showed the coexistence of multiple mechanisms of splicing alterations for seven variants. A leaky effect on splicing was documented in one de novo substitution detected in a sporadic patient with a specific phenotype without neurofibromas. Our splicing assay proved to be a reliable and fast method to validate novel NF1 variants potentially affecting splicing and to detect hypomorphic effects that might have phenotypic consequences, avoiding the requirement of patient’s RNA.
Alicia Bach, Jingyi Mi, Matthew Hunter, Benjamin J. Halliday, Sixto García-Miñaúr, Francesca Sperotto, Eva Trevisson, David Markie, Ian M. Morison, Marwan Shinawi,et al.
Springer Science and Business Media LLC
G. Bottesi, A. Spoto, E. Trevisson, D. Zuccarello, G. Vidotto, M. Cassina, and M. Clementi
Oxford University Press (OUP)
Low skin‐related quality of life (QoL) is usually associated with low levels of self‐confidence and self‐esteem and with high levels of anxiety and depression symptoms. The way patients cope with a physical disease impacts significantly on their psychosocial adjustment to the disorder and on their emotional functioning.
D. Gareth R. Evans, Roope A. Kallionpää, Maurizio Clementi, Eva Trevisson, Victor-Felix Mautner, Sacha J. Howell, Lauren Lewis, Ouidad Zehou, Sirkku Peltonen, Antonella Brunello,et al.
Elsevier BV
D. Gareth R. Evans, Roope A. Kallionpää, Maurizio Clementi, Eva Trevisson, Victor-Felix Mautner, Sacha J. Howell, Lauren Lewis, Ouidad Zehou, Sirkku Peltonen, Antonella Brunello,et al.
Elsevier BV
Magdalena Koczkowska, Tom Callens, Yunjia Chen, Alicia Gomes, Alesha D. Hicks, Angela Sharp, Eric Johns, Kim Armfield Uhas, Linlea Armstrong, Katherine Armstrong Bosanko,et al.
Hindawi Limited
We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5–31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan‐like phenotype, which is significantly more compared with the “classic” NF1‐affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with “classic” NF1‐affected cohorts. However, p.Met1149‐positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype–phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
Cristina Cerqua, Alberto Casarin, Fabien Pierrel, Luis Vazquez Fonseca, Giampiero Viola, Leonardo Salviati, and Eva Trevisson
Springer Science and Business Media LLC
AbstractCoenzyme Q10 (CoQ10) deficiencies are a group of heterogeneous conditions that respond to ubiquinone administration if treated soon after the onset of symptoms. However, this treatment is only partially effective due to its poor bioavailability. We tested whether vitamin K2, which was reported to act as a mitochondrial electron carrier in D. melanogaster, could mimic ubiquinone function in human CoQ10 deficient cell lines, and in yeast carrying mutations in genes required for coenzyme Q6 (CoQ6) biosynthesis. We found that vitamin K2, despite entering into mitochondria, restored neither electron flow in the respiratory chain, nor ATP synthesis. Conversely, coenzyme Q4 (CoQ4), an analog of CoQ10 with a shorter isoprenoid side chain, could efficiently substitute its function. Given its better solubility, CoQ4 could represent an alternative to CoQ10 in patients with both primary and secondary CoQ10 deficiencies.