Giacomina Rossi

Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milano, Lombardy, Italy

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Publications (34)164.04 Total impact

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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) is a very heterogeneous disorder. It is genetically linked to three major genes: microtubule-associated protein tau (MAPT), progranulin (GRN), and C9ORF72. In particular, mutations in GRN account for 5-10% of all cases and give rise to a wide spectrum of clinical phenotypes, ranging from behavioral frontotemporal dementia (bvFTD) to primary progressive aphasia, including progressive non fluent aphasia (PNFA) and semantic dementia, and corticobasal syndrome (CBS). We studied a family affected by FTLD whose members showed three different phenotypes: bvFTD, PNFA, and CBS. We performed plasma progranulin measurement before any genetic analyses and, due to the low level detected, we sequenced GRN and found the new mutation EX0-5' splice site A > G in the 5'-UTR region, where no pathogenic mutations had been previously demonstrated. Genetic analyses of MAPT and C9ORF72 were normal. GRN mRNA expression showed about 50% reduction caused by this mutation, and similar results were found for progranulin level. Testing of nonsense mediated RNA decay gave negative results, suggesting a different mechanism of mRNA degradation. In summary, the EX0-5' splice site A > G mutation widens the GRN regions affected by null mutations, including the 5'-UTR, and confirms once more the large phenotypic variability linked to GRN mutations.
    Journal of Alzheimer's disease: JAD 07/2014; · 4.17 Impact Factor
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    ABSTRACT: Tau is a major microtubule-associated protein in brain neurons. Its misfolding and accumulation cause neurodegenerative diseases characterized by brain atrophy and dementia, named tauopathies. Genetic forms are caused by mutations of microtubule-associated protein tau gene (MAPT). Tau is expressed also in nonneural tissues such as lymphocytes. Tau has been recently recognized as a multifunctional protein, and in particular, some findings supported a role in genome stability. In fact, peripheral cells of patients affected by frontotemporal dementia carrying different MAPT mutations showed structural and numerical chromosome aberrations. The aim of this study was to assess chromosome stability in peripheral cell from two animal models of genetic tauopathy, JNPL3 and PS19 mouse strains expressing the human tau carrying the P301L and P301S mutations, respectively, to confirm the previous data on humans. After demonstrating the presence of mutated tau in spleen, we performed standard cytogenetic analysis of splenic lymphocytes from homozygous and hemizygous JNPL3, hemizygous PS19, and relevant controls. Losses and gains of chromosomes (aneuploidy) were evaluated. We detected a significantly higher level of aneuploidy in JNPL3 and PS19 than in control mice. Moreover, in JNPL3, the aneuploidy was higher in homozygotes than in hemizygotes, demonstrating a gene dose effect, which appeared also to be age independent. Our results show that mutated tau is associated with chromosome instability. It is conceivable to hypothesize that in genetic tauopathies the aneuploidy may be present also in central nervous system, possibly contributing to neurodegeneration.
    Neurogenetics 11/2013; · 3.58 Impact Factor
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    ABSTRACT: Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as the most common pathogenic mutation in families with autosomal dominant frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. Herein we investigated frequency and penetrance of the C9ORF72 hexanucleotide repeat pathological expansion in a large cohort of familial and sporadic FTLD and related disorders (FTLD and related disorders, n = 388; Controls, n = 201). Moreover, we weighed the impact of C9ORF72 genotype on clinical phenotype taking into account the hexanucleotide repeat units number as a possible disease modifier. In our cohort, the C9ORF72 pathological expansion: i) showed a prevalence of 7.5%; ii) showed a full penetrance by the age of 80; iii) was rarely found in sporadic patients; iv) was solely associated with FTLD; v) was mainly associated with bvFTD clinical subtype; and vi) was associated with earlier age of onset in the youngest generation compared with the previous generation within a pedigree. Interestingly, intermediate C9ORF72 expansion had a risk effect in familial/sporadic FTLD. Eventually, the C9ORF72 repeat units number influenced the disease phenotype in terms of age of onset and associated clinical subtype. Genome-wide studies in well characterized clinical cohorts will be essential in order to decipher pathways of disease expression in C9ORF72-associated neurodegeneration.
    Journal of Alzheimer's disease: JAD 09/2013; · 4.17 Impact Factor
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    ABSTRACT: Microtubule-associated protein tau gene (MAPT) is one of the major genes linked to frontotemporal lobar degeneration, a group of neurodegenerative diseases clinically, pathologically, and genetically heterogeneous. In particular, MAPT mutations give rise to the subgroup of tauopathies. The pathogenetic mechanisms underlying the MAPT mutations so far described are the decreased ability of tau protein to promote microtubule polymerization (missense mutations) or the altered ratio of tau isoforms (splicing mutations), both leading to accumulation of hyperphosphorylated filamentous tau protein. Following a genetic screening of patients affected by frontotemporal lobar degeneration, we identified 2 MAPT mutations, V363I and V363A, leading to atypical clinical phenotypes, such as posterior cortical atrophy. We investigated in vitro features of the recombinant mutated tau isoforms and revealed unusual functional and structural characteristics such as an increased ability to promote microtubule polymerization and a tendency to form oligomeric instead of filamentous aggregates. Thus, we disclosed a greater than expected complexity of abnormal features of mutated tau isoforms. Overall our findings suggest a high probability that these mutations are pathogenic.
    Neurobiology of aging 09/2013; · 5.94 Impact Factor
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    ABSTRACT: In addition to the main function of promoting polymerization and stabilization of microtubules, other roles are being attributed to tau, now considered a multifunctional protein. In particular, previous studies suggest that tau is involved in chromosome stability and genome protection. We performed cytogenetic analysis, including molecular karyotyping, on lymphocytes and fibroblasts from patients affected by frontotemporal lobar degeneration carrying different mutations in the microtubule-associated protein tau gene, to investigate the effects of these mutations on genome stability. Furthermore, we analyzed the response of mutated lymphoblastoid cell lines to genotoxic agents to evaluate the participation of tau to DNA repair systems. We found a significantly higher level of chromosome aberrations in mutated than in control cells. Mutated lymphocytes showed higher percentages of stable lesions, clonal and total aneuploidy (medians: 2 versus 0, p $\ll$ 0.01; 1.5 versus 0, p $\ll$ 0.01; 16.5 versus 0, p $\ll$ 0.01, respectively). Fibroblasts of patients showed higher percentages of stable lesions, structural aberrations and total aneuploidy (medians: 0 versus 0, p = 0.03; 5.8 versus 0, p = 0.02; 26.5 versus 12.6, p $\ll$ 0.01, respectively). In addition, the in depth analysis of DNA copy number variations showed a higher tendency to non-allelic homologous recombination in mutated cells. Finally, while our analysis did not support an involvement of tau in DNA repair systems, it revealed its role in stabilization of chromatin. In summary, our findings indicate a role of tau in genome and chromosome stability that can be ascribed to its function as a microtubule-associated protein as well as a protein protecting chromatin integrity through interaction with DNA.
    Journal of Alzheimer's disease: JAD 10/2012; · 4.17 Impact Factor
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    ABSTRACT: We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and 2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.
    The American Journal of Human Genetics 05/2012; 90(6):1102-7. · 11.20 Impact Factor
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    ABSTRACT: Recently, attention was drawn to a role for progranulin in the central nervous system with the identification of mutations in the progranulin gene (GRN) as an important cause of frontotemporal lobar degeneration. GRN mutations are associated with a strong reduction of circulating progranulin and widely variable clinical phenotypes: thus, the dosage of plasma progranulin is a useful tool for a quick and inexpensive large-scale screening of carriers of GRN mutations. To establish the best cutoff threshold for normal versus abnormal levels of plasma progranulin. 309 cognitively healthy controls (25-87 years of age), 72 affected and unaffected GRN+ null mutation carriers (24-86 years of age), 3 affected GRN missense mutation carriers, 342 patients with neurodegenerative diseases and 293 subjects with mild cognitive impairment were enrolled at the Memory Clinic, IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy, and at the Alzheimer Unit, Ospedale Maggiore Policlinico and IRCCS Istituto Neurologico C. Besta, Milan, Italy. Plasma progranulin levels were measured using an ELISA kit (AdipoGen Inc., Seoul, Korea). Plasma progranulin did not correlate with age, gender or body mass index. We established a new plasma progranulin protein cutoff level of 61.55 ng/ml that identifies, with a specificity of 99.6% and a sensitivity of 95.8%, null mutation carriers among subjects attending to a memory clinic. Affected and unaffected GRN null mutation carriers did not differ in terms of circulating progranulin protein (p = 0.686). A significant disease anticipation was observed in GRN+ subjects with the lowest progranulin levels. We propose a new plasma progranulin protein cutoff level useful for clinical practice.
    Neurodegenerative Diseases 11/2011; 9(3):121-7. · 3.41 Impact Factor
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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) can be sporadic or familial. The genes encoding the microtubule-associated protein tau (MAPT) and progranulin (GRN) are the most relevant genes so far known causing the hereditary forms. Following genetic screening of patients affected by FTLD, we identified 2 new MAPT mutations, P364S and G366R, the former in a sporadic case. In the study we report the clinical and genetic features of the patients carrying these mutations, and the functional effects of the mutations, analyzed in vitro in order to investigate their pathogenic character. Both mutations resulted in reduced ability of tau to promote microtubule polymerization; the P364S protein variant also showed a high propensity to aggregate into filaments. These results suggest a high probability that these mutations are pathogenic. Our findings highlight the importance of genetic analysis also in sporadic forms of FTLD, and the role of in vitro studies to evaluate the pathologic features of new mutations.
    Neurobiology of aging 09/2011; 33(4):834.e1-6. · 5.94 Impact Factor
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    ABSTRACT: Cortico-basal syndrome (CBS) is a rare neurodegenerative disease characterised by movement and cognitive disorders. It occurs along the spectrum of fronto-temporal lobar degeneration (FTLD), which also includes fronto-temporal dementia (FTD) and progressive supranuclear palsy (PSP). FTLD has recently been shown to be associated with mutations in GRN gene, coding for progranulin, a multifunctional secreted glycoprotein involved in cell cycle, inflammation and tissue repair. We describe the case of a 73-year-old man suffering from CBS with a family history of cognitive disorders belonging to the clinical spectrum of FTLD. Sequencing analysis of GRN in this patient revealed that the C157KfsX97 null mutation has been already described by Le Ber et al. in a French patient affected by an apparently sporadic form of FTD. This report confirms the variability of clinical phenotypes associated with the same mutation and emphasises the importance of genetic analysis in cases with a clear familiarity, as well as in apparently sporadic forms.
    Neurological Sciences 06/2011; 33(1):93-7. · 1.41 Impact Factor
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    ABSTRACT: Mutations in the progranulin gene (GRN) were recently identified as an important cause of familial frontotemporal dementia (FTD). More than 60 pathogenic mutations have been reported up to now and prominent phenotypic variability within and among affected kindreds has been described. We have studied an Italian family with clinical evidence of dementia, and here we report detailed clinical records, imaging, sequential neurological examinations, cognitive assessments, and genetic analysis of three affected members of the same generation. Genetic analysis revealed the presence of the null mutation IVS6 + 5_8delGTGA in GRN, leading to haploinsufficiency, as documented by mRNA analysis. The mutation is associated with wide variation of the clinical phenotype, ranging from FTD to Alzheimer's disease and to a rapidly-progressive dementia. In summary, the patients of this kindred showed highly variable clinical features that do not have a close correspondence with the pattern of the cerebral atrophy. Our data extend the phenotypic spectrum and the complexity of neurodegenerative diseases linked to GRN mutations.
    Journal of Alzheimer's disease: JAD 06/2011; 26(3):583-90. · 4.17 Impact Factor
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2011; 7(4).
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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by behavioural disturbances and cognitive decline. Here we describe an Italian family with FTLD showing remarkable phenotypic heterogeneity. Based on low plasma levels of progranulin, we analyzed the progranulin gene (GRN) in two patients with early onset and found the novel frame-shift mutation T278SfsX7. mRNA analysis confirmed the null effect of the mutation. The patients were homozygous for H1 MAPT haplotype, a disease modifier factor that can account for early age at onset. Being predictive for GRN null mutations, plasma progranulin dosage should be included in diagnostic work-up of dementia.
    Journal of Alzheimer's disease: JAD 10/2010; 23(1):7-12. · 4.17 Impact Factor
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    ABSTRACT: To report the clinical, genetic, neuroimaging, and neuropathologic studies of patients with the hereditary cerebral hemorrhage with amyloidosis linked to the APP E693K mutation. Case series. Clinical details and laboratory results were collected by direct evaluation and previous medical records. DNA analysis was carried out in several affected subjects and healthy individuals. Neuropathologic examination was performed in 2 subjects. Southern Lombardy, Italy. Patients Individuals with and without amyloidosis in 4 unrelated Italian families (N = 37). Main Outcome Measure Genotype-phenotype relationship. The affected individuals presented with recurrent headache and multiple strokes, followed by epilepsy and cognitive decline in most of them. The disease was inherited with an autosomal dominant trait and segregated with the APP E693K mutation. Neuroimaging demonstrated small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts, and leukoaraiosis. Amyloid-beta immunoreactivity was detected in the wall of leptomeningeal and parenchymal vessels and in the neuropil, whereas phosphorylated tau, neurofibrillary changes, and neuritic plaques were absent. These findings expand the number of APP mutations linked to hereditary cerebral hemorrhage with amyloidosis, reinforcing the link between this phenotype and codon 693 of APP.
    Archives of neurology 08/2010; 67(8):987-95. · 7.58 Impact Factor
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2010; 6(4).
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    ABSTRACT: Presenilin mutations are the main cause of familial Alzheimer's disease. So far, more than 160 mutations in the Presenilin 1 gene (PSEN1) and approximately 10 mutations in the homologous Presenilin 2 gene (PSEN2) have been identified. Some PSEN1 mutations are associated with a phenotype fulfilling the clinical criteria of frontotemporal dementia. In PSEN2, T122P and M239V mutations presented with severe behavioral disturbances. We describe an Italian patient with a novel PSEN2 mutation (Y231C) who showed behavioral abnormalities and language impairment as presenting symptoms, with later involvement of other cognitive abilities, particularly of posterior functions.
    Journal of Alzheimer's disease: JAD 04/2009; 16(3):509-11. · 4.17 Impact Factor
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    ABSTRACT: beta-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673-->valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced beta-amyloid (Abeta) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Abeta aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.
    Science 04/2009; 323(5920):1473-7. · 31.20 Impact Factor
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    ABSTRACT: OBJECTIVE: To describe a new dementia phenotype of Gerstmann-Straussler-Scheinker disease (GSS) in a previously unreported Italian family. Design Longitudinal clinical and neuropsychological assessment, combined with magnetic resonance imaging (MRI), single positron emission tomography (SPECT) and molecular genetic studies. Setting Neuropsychology Laboratory, and Division of Neuropathology and Neurology, "C. Besta" National Neurological Institute. Patients and participants Three members of the family. Measurements and results. Standardised neuropsychological tests were used to determine cognitive patterns. The proband had a history of primary dementia characterised by loss of initiative, planning, behaviour control, awareness, language and memory; the two relatives suffered from progressive ataxia. MRI of the demented patient revealed brain atrophy with a hyperintense signal in the frontal cortex; SPECT revealed decreased perfusion in the left temporal and parietal cortex and left thalamus. The two ataxic patients showed cerebellar atrophy with no signs of altered perfusion. Analysis of the PRNP gene showed a proline/leucine substitution at codon 102 in all three patients, associated with methionine/valine heterozygosity at the polymorphic codon 129. Conclusions Primary dementia with prominent frontotemporal signs is a new phenotypical expression of P102L-related GSS that coexists in the same family with the ataxic form of the disease. This remarkable variability suggests that still unidentified genetic or acquired factors may modulate the manifestations of GSS. Genetic examination of the PRNP should be included in the diagnostic work-up of patients with poorly classifiable dementia.
    Neurological Sciences 12/2008; 29(6):405-10. · 1.41 Impact Factor
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    ABSTRACT: A few patients with mutations in the microtubule-associated protein tau gene (MAPT), affected by frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T), may clinically present with a corticobasal syndrome (CBS). We report a case of apparently sporadic CBS bearing a mutation in the MAPT gene so far associated with frontotemporal dementia (FTD) phenotype. The patient is a 41-year-old man with progressive asymmetric signs of cortical and basal ganglia involvement consistent with CBS. Magnetic resonance imaging showed asymmetric cortical atrophy and unusual corticospinal tract hyperintensity in T2-weighted images. Genetic testing revealed a heterozygous G to C mutation at the first base of codon 389 of the MAPT gene, changing glycine to arginine (G389R), in the patient and his unaffected elderly father. In conclusion, the MAPT G389R mutation shows phenotypic variability resulting in both FTD and CBS. The mutation also demonstrates incomplete penetrance. Corticospinal tract degeneration is an exceptional finding.
    Movement Disorders 05/2008; 23(6):892-5. · 5.63 Impact Factor
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    ABSTRACT: Tau is a microtubule-associated protein that promotes assembly and stabilization of cytoskeleton microtubules. It is mostly expressed in neuronal and glial cells but it is also present in non-neural cells such as fibroblasts and lymphocytes. An altered tau produces cytoskeleton pathology resulting in neurodegenerative diseases such as Alzheimer's disease and tauopathies. Tau has been suggested to be a multifunctional protein, due to its localization in different cellular compartments. However its further functions are still unclear. We analyzed the distribution of tau in human skin fibroblasts showing its localization in the nucleus and along mitotic chromosomes. Then, we investigated if an altered tau, such as the P301L mutated protein associated with frontotemporal dementia, could produce nuclear pathology. We found that patients carrying the mutation consistently had several chromosome aberrations in their fibroblasts and lymphocytes: chromosome and chromatid breakages or gaps, aneuploidies, translocations, in addition to chromatin bridges and decondensed chromosomes. Our findings argue for a role of tau in chromosome stability by means of its interaction with both microtubules and chromatin.
    Cell cycle (Georgetown, Tex.) 04/2008; 7(12):1788-94. · 5.24 Impact Factor
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    ABSTRACT: There is a large amount of tissue stored in brain collections and brain banks, but little is known about whether formalin-fixed tissues and paraffin blocks stored for years in brain banks are suitable for the retrospective genetic studies. The study was carried out in order to: (i) compare DNA preservation in frozen, formalin-fixed and paraffin-embedded tissues stored for different periods; (ii) study point mutations and triplet expansions in frozen, formalin-fixed and paraffin-embedded material stored for variable periods, and using different fixative solutions; (iii) compare different methods to optimize DNA extraction and DNA amplification from suboptimally preserved brain tissue. DNA preservation is suitable for genetic studies in samples stored at -80 degrees C for several years. Formalin-fixed, paraffin-embedded tissue was inferior to frozen tissue, but did yield adequate results in many cases depending on the type of fixative solution and time of fixation before embedding. Prolonged fixation in formalin rarely yielded useful DNA. Similar results were obtained in samples from prion diseases. The best results were obtained by using the Qiagen kits (QIAmp DNA Micro) in frozen material, paraffin blocks and formalin-fixed tissue. Genomiphi and TaKaRa Ex Taq methods were also assayed in paraffin blocks and in formalin-fixed samples with limited success.
    Brain Pathology 08/2007; 17(3):297-303. · 4.74 Impact Factor

Publication Stats

456 Citations
164.04 Total Impact Points

Institutions

  • 2002–2014
    • Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
      • Division of Neuropathology
      Milano, Lombardy, Italy
    • University of Milan
      • Istituto di Fisiologia Veterinaria e Biochimica
      Milano, Lombardy, Italy
  • 2004–2012
    • Foundation of the Carlo Besta Neurological Institute
      Milano, Lombardy, Italy
  • 2011
    • University of Udine
      Udine, Friuli Venezia Giulia, Italy
  • 2005
    • Second University of Naples
      Caserta, Campania, Italy