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Pasquale Striano,
Antonietta Coppola,
Roberta Paravidino,
Michela Malacarne,
Stefania Gimelli,
Angela Robbiano,
Monica Traverso,
Marianna Pezzella,
Vincenzo Belcastro,
Amedeo Bianchi, [......],
Margherita Silengo,
Maria Luigia Cavaliere,
Matteo Benelli,
Alberto Magi,
Maria Piccione, Franca Dagna Bricarelli,
Domenico A Coviello,
Marco Fichera,
Carlo Minetti,
Federico Zara
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ABSTRACT: To perform an extensive search for genomic rearrangements by microarray-based comparative genomic hybridization in patients with epilepsy.
Prospective cohort study.
Epilepsy centers in Italy.
Two hundred seventy-nine patients with unexplained epilepsy, 265 individuals with nonsyndromic mental retardation but no epilepsy, and 246 healthy control subjects were screened by microarray-based comparative genomic hybridization.
Identification of copy number variations (CNVs) and gene enrichment.
Rare CNVs occurred in 26 patients (9.3%) and 16 healthy control subjects (6.5%) (P = .26). The CNVs identified in patients were larger (P = .03) and showed higher gene content (P = .02) than those in control subjects. The CNVs larger than 1 megabase (P = .002) and including more than 10 genes (P = .005) occurred more frequently in patients than in control subjects. Nine patients (34.6%) among those harboring rare CNVs showed rearrangements associated with emerging microdeletion or microduplication syndromes. Mental retardation and neuropsychiatric features were associated with rare CNVs (P = .004), whereas epilepsy type was not. The CNV rate in patients with epilepsy and mental retardation or neuropsychiatric features is not different from that observed in patients with mental retardation only. Moreover, significant enrichment of genes involved in ion transport was observed within CNVs identified in patients with epilepsy.
Patients with epilepsy show a significantly increased burden of large, rare, gene-rich CNVs, particularly when associated with mental retardation and neuropsychiatric features. The limited overlap between CNVs observed in the epilepsy group and those observed in the group with mental retardation only as well as the involvement of specific (ion channel) genes indicate a specific association between the identified CNVs and epilepsy. Screening for CNVs should be performed for diagnostic purposes preferentially in patients with epilepsy and mental retardation or neuropsychiatric features.
Archives of neurology 11/2011; 69(3):322-30. · 6.31 Impact Factor
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Antonio Falace,
Fabia Filipello,
Veronica La Padula,
Nicola Vanni,
Francesca Madia,
Davide De Pietri Tonelli,
Fabrizio A de Falco,
Pasquale Striano, Franca Dagna Bricarelli,
Carlo Minetti,
Fabio Benfenati,
Anna Fassio,
Federico Zara
[show abstract]
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ABSTRACT: Idiopathic epilepsies (IEs) are a group of disorders characterized by recurrent seizures in the absence of detectable brain lesions or metabolic abnormalities. IEs include common disorders with a complex mode of inheritance and rare Mendelian traits suggesting the occurrence of several alleles with variable penetrance. We previously described a large family with a recessive form of idiopathic epilepsy, named familial infantile myoclonic epilepsy (FIME), and mapped the disease locus on chromosome 16p13.3 by linkage analysis. In the present study, we found that two compound heterozygous missense mutations (D147H and A509V) in TBC1D24, a gene of unknown function, are responsible for FIME. In situ hybridization analysis revealed that Tbc1d24 is mainly expressed at the level of the cerebral cortex and the hippocampus. By coimmunoprecipitation assay we found that TBC1D24 binds ARF6, a Ras-related family of small GTPases regulating exo-endocytosis dynamics. The main recognized function of ARF6 in the nervous system is the regulation of dendritic branching, spine formation, and axonal extension. TBC1D24 overexpression resulted in a significant increase in neurite length and arborization and the FIME mutations significantly reverted this phenotype. In this study we identified a gene mutation involved in autosomal-recessive idiopathic epilepsy, unveiled the involvement of ARF6-dependent molecular pathway in brain hyperexcitability and seizures, and confirmed the emerging role of subtle cytoarchitectural alterations in the etiology of this group of common epileptic disorders.
The American Journal of Human Genetics 09/2010; 87(3):365-70. · 10.60 Impact Factor
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Louise E Reynolds,
Alan R Watson,
Marianne Baker,
Tania A Jones,
Gabriela D'Amico,
Stephen D Robinson,
Carine Joffre,
Sarah Garrido-Urbani,
Juan Carlos Rodriguez-Manzaneque,
Estefanía Martino-Echarri, [......],
Dean Nizetic,
Christopher J McCabe,
Andrew S Turnell,
Stephanie Kermorgant,
Beat A Imhof,
Ralf H Adams,
Elizabeth M C Fisher,
Victor L J Tybulewicz,
Ian R Hart,
Kairbaan M Hodivala-Dilke
Nature 07/2010; 466(7304):398. · 36.28 Impact Factor
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Louise E Reynolds,
Alan R Watson,
Marianne Baker,
Tania A Jones,
Gabriela D'Amico,
Stephen D Robinson,
Carine Joffre,
Sarah Garrido-Urbani,
Juan Carlos Rodriguez-Manzaneque,
Estefanía Martino-Echarri, [......],
Dean Nizetic,
Christopher J McCabe,
Andrew S Turnell,
Stephanie Kermorgant,
Beat A Imhof,
Ralf Adams,
Elizabeth M C Fisher,
Victor L J Tybulewicz,
Ian R Hart,
Kairbaan M Hodivala-Dilke
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ABSTRACT: Down's syndrome (DS) is a genetic disorder caused by full or partial trisomy of human chromosome 21 and presents with many clinical phenotypes including a reduced incidence of solid tumours. Recent work with the Ts65Dn model of DS, which has orthologues of about 50% of the genes on chromosome 21 (Hsa21), has indicated that three copies of the ETS2 (ref. 3) or DS candidate region 1 (DSCR1) genes (a previously known suppressor of angiogenesis) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses roughly 81% of Hsa21 genes but not the human DSCR1 region. We transplanted B16F0 and Lewis lung carcinoma tumour cells into Tc1 mice and showed that growth of these tumours was substantially reduced compared with wild-type littermate controls. Furthermore, tumour angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS1and ERG) and novel endothelial cell-specific genes, never previously shown to be involved in angiogenesis (JAM-B and PTTG1IP), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis, explaining the reduced tumour growth in DS. Furthermore, we expect that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will permit the identification of other endothelium-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients.
Nature 06/2010; 465(7299):813-7. · 36.28 Impact Factor
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[show abstract]
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ABSTRACT: Array comparative genomic hybridization (aCGH) is a microarray technology that allows one to detect and map genomic alterations. The standard workflow of the aCGH data analysis consists of 2 steps: detecting the boundaries of the regions of changed copy number by means of a segmentation algorithm (break point identification) and then labeling each region as loss, neutral, or gain with a probabilistic framework (calling procedure). In this paper, we introduce a novel calling procedure based on a mixture of truncated normal distributions, named FastCall, that aims to give aberration probabilities to segmented aCGH data in a very fast and accurate way. Both on synthetic and real aCGH data, FastCall obtains excellent performances in terms of classification accuracy and running time.
Biostatistics 03/2010; 11(3):515-8. · 2.14 Impact Factor
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American Journal of Medical Genetics Part A 12/2008; 146A(23):3095-9. · 2.39 Impact Factor
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[show abstract]
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ABSTRACT: Down syndrome, caused by the trisomy of chromosome 21, is a complex condition characterized by a number of phenotypic features, including reduced neuron number and synaptic plasticity, early Alzheimer disease-like neurodegeneration, craniofacial dysmorphia, heart development defects, increased incidence of childhood leukemia, and powerful suppression of the incidence of most solid tumors. Mouse models replicate a number of these phenotypes. The Tc1 Down syndrome model was constructed by introducing a single supernumerary human chromosome 21 into a mouse embryonic stem cell, and it reproduces a large number of Down syndrome phenotypes including heart development defects. However, little is still known about the developmental onset of the trisomy 21-induced mechanisms behind these phenotypes or the proteins that are responsible for them. This study determined the proteomic differences that are present in undifferentiated embryonic stem cells and are caused by an additional human chromosome 21. A total of 1661 proteins were identified using two-dimensional liquid chromatography followed by tandem mass spectrometry from whole embryonic stem cell lysates. Using isobaric tags for relative and absolute quantification, we found 52 proteins that differed in expression by greater than two standard deviations from the mean when an extra human chromosome 21 was present. Of these, at least 11 have a possible functional association with a Down syndrome phenotype or a human chromosome 21-encoded gene. This study also showed that quantitative protein expression differences in embryonic stem cells can persist to adult mouse as well as reproduce in human Down syndrome fetal tissue. This indicates that changes that are determined in embryonic stem cells of Down syndrome could potentially identify proteins that are involved in phenotypes of Down syndrome, and it shows that these cell lines can be used for the purpose of studying these pathomechanisms.
Molecular & Cellular Proteomics 12/2008; 8(4):585-95. · 7.40 Impact Factor
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Vincenzo Falbo,
Giovanna Floridia,
Fabrizio Tosto,
Federica Censi,
Marco Salvatore,
Anna Ravani,
Alessandra Ferlini,
Maria Antonietta Melis,
Marina Grasso, Franca Dagna Bricarelli,
Domenica Taruscio
[show abstract]
[hide abstract]
ABSTRACT: The Italian External Quality Assessment scheme for fragile X syndrome started in 2001 as an activity funded by the National Health System and coordinated by the National Institute of Public Health. The aim of this work is to present the data of 5 years (2001--2004 and 2006) of survey. The External Quality Assessment scheme was designed to cover the following points: (a) genotyping and (b) interpretation and reporting of results. Overall, the scheme covered about 65% of all Italian public laboratories. The average reporting of results was 91.6%, with an overall success rate of 76%. The rate of diagnostic errors observed was on average 5%. Inaccuracy in sizing of CGG repeats of normal and premutated alleles was reported. During the survey the proportion of laboratories using a Southern blotting, polymerase chain reaction, and ABI sizing kit in combination rose from 36.8% to 70.6%. The reports from laboratories showed incompleteness and considerable variations in expected outcomes. For this reason, in 2004 a model for written reports was introduced. In conclusion, these data underscore the need to participate in External Quality Assessment schemes as an educational resource to ensure quality in molecular genetic testing.
Genetic Testing 07/2008; 12(2):279-88. · 1.17 Impact Factor
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ABSTRACT: The molecular diagnosis of fragile X syndrome relies on the detection of the pathogenic CGG repeat expansion in the FMR1 gene. Deletions and point mutations have occasionally been reported. Rare polymorphisms might mimic a deletion by Southern blot analysis, leading to false-positive results. We describe a novel rare nucleotide substitution within the CGG repeat. The proband was a woman with a positive family history of mental retardation. Southern blot analysis showed an additional band consistent with a deletion in the region detected by the StB12.3 probe. Sequencing of this region revealed a G>C transversion that interrupts the CGG repeat and introduces an EagI site. The same variant was observed in both the healthy son and father of the proband, supporting the hypothesis that the nucleotide substitution is a silent polymorphism, the frequency of which we estimated to be less than 1% in the general population. These findings argue for a pathogenic role of nucleotide variants within the CGG repeat and suggest possible consequences of unexpected findings in the molecular diagnostics of fragile X syndrome. Thus, although the sequence context of a single nucleotide substitution may not predict possible effects on mRNA or protein function, a specific change in the higher order structures of DNA or mRNA may be functionally relevant in the pathological phenotype.
Journal of Molecular Diagnostics 06/2008; 10(3):272-5. · 3.58 Impact Factor
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Nadia Sessarego,
Alessia Parodi,
Marina Podestà,
Federica Benvenuto,
Massimo Mogni,
Valentina Raviolo,
Mario Lituania,
Annalisa Kunkl,
Guido Ferlazzo, Franca Dagna Bricarelli,
Antonio Uccelli,
Francesco Frassoni
[show abstract]
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ABSTRACT: Mesenchymal stromal cells are multipotent cells considered to be of great promise for use in regenerative medicine. However, the cell dose may be a critical factor in many clinical conditions and the yield resulting from the ex vivo expansion of mesenchymal stromal cells derived from bone marrow may be insufficient. Thus, alternative sources of mesenchymal stromal cells need to be explored. In this study, mesenchymal stromal cells were successfully isolated from second trimester amniotic fluid and analyzed for chromosomal stability to validate their safety for potential utilization as a cell therapy product.
Mesenchymal stromal cells were expanded up to the sixth passage starting from amniotic fluid using different culture conditions to optimize large-scale production.
The highest number of mesenchymal stromal cells derived from amniotic fluid was reached at a low plating density; in these conditions the expansion of mesenchymal stromal cells from amniotic fluid was significantly greater than that of adult bone marrow-derived mesenchymal stromal cells. Mesenchymal stromal cells from amniotic fluid represent a relatively homogeneous population of immature cells with immunosuppressive properties and extensive proliferative potential. Despite their high proliferative capacity in culture, we did not observe any karyotypic abnormalities or transformation potential in vitro nor any tumorigenic effect in vivo.
Fetal mesenchymal stromal cells can be extensively expanded from amniotic fluid, showing no karyotypic abnormalities or transformation potential in vitro and no tumorigenic effect in vivo. They represent a relatively homogeneous population of immature mesenchymal stromal cells with long telomeres, immunosuppressive properties and extensive proliferative potential. Our results indicate that amniotic fluid represents a rich source of mesenchymal stromal cells suitable for banking to be used when large amounts of cells are required.
Haematologica 04/2008; 93(3):339-46. · 6.42 Impact Factor
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Mirko Corselli,
Alessia Parodi,
Massimo Mogni,
Nadia Sessarego,
Annalisa Kunkl, Franca Dagna-Bricarelli,
Adalberto Ibatici,
Sarah Pozzi,
Andrea Bacigalupo,
Francesco Frassoni,
Giovanna Piaggio
[show abstract]
[hide abstract]
ABSTRACT: Endothelial progenitor cells (EPCs) are involved in neovessel formation. So far, therapeutic angiogenesis is hampered by the low frequency and limited proliferative potential of these cells isolated from peripheral blood. Recently, it has been shown that cord blood-derived EPCs (CB EPCs) can be ex vivo expanded on a clinical scale. In this study, we evaluated the expansion potential of CB EPCs together with their phenotypic, functional, and chromosomal stability over time.
Flow cytometry, in vitro tube formation, and proliferation assays were performed to characterize CB EPC-derived cells. Chromosomal stability was evaluated by karyotype analysis. In vitro and in vivo tumorigenicity was evaluated by soft agar assay and injection into nonobese diabetic/severe combined immunodeficient mice, respectively.
We showed that CB EPC-derived cells displayed phenotypic and functional features of EPCs, although a process of maturation was observed over time. Although we confirmed that CB EPCs have a greater expansion potential compared to peripheral blood EPCS, we observed a high incidence of cytogenetic alterations (71%) in the expanded endothelial cell population, even at early times of culture. In two cases, spontaneous transformation in vitro was documented, but none of the samples tested showed tumorigenic potential in vivo. Conversely, no karyotype alterations have been observed on peripheral blood EPCs-derived cells.
We confirm that CB represents a good source for clinical ex vivo expansion of EPCs. However, because of high frequency of karyotype alterations, these cells cannot be considered free of risk in clinical application.
Experimental Hematology 04/2008; 36(3):340-9. · 2.90 Impact Factor
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Paola Prandini,
Samuel Deutsch,
Robert Lyle,
Maryline Gagnebin,
Celine Delucinge Vivier,
Mauro Delorenzi,
Corinne Gehrig,
Patrick Descombes,
Stephanie Sherman, Franca Dagna Bricarelli,
Chiara Baldo,
Antonio Novelli,
Bruno Dallapiccola,
Stylianos E Antonarakis
[show abstract]
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ABSTRACT: Down syndrome (DS) is characterized by extensive phenotypic variability, with most traits occurring in only a fraction of affected individuals. Substantial gene-expression variation is present among unaffected individuals, and this variation has a strong genetic component. Since DS is caused by genomic-dosage imbalance, we hypothesize that gene-expression variation of human chromosome 21 (HSA21) genes in individuals with DS has an impact on the phenotypic variability among affected individuals. We studied gene-expression variation in 14 lymphoblastoid and 17 fibroblast cell lines from individuals with DS and an equal number of controls. Gene expression was assayed using quantitative real-time polymerase chain reaction on 100 and 106 HSA21 genes and 23 and 26 non-HSA21 genes in lymphoblastoid and fibroblast cell lines, respectively. Surprisingly, only 39% and 62% of HSA21 genes in lymphoblastoid and fibroblast cells, respectively, showed a statistically significant difference between DS and normal samples, although the average up-regulation of HSA21 genes was close to the expected 1.5-fold in both cell types. Gene-expression variation in DS and normal samples was evaluated using the Kolmogorov-Smirnov test. According to the degree of overlap in expression levels, we classified all genes into 3 groups: (A) nonoverlapping, (B) partially overlapping, and (C) extensively overlapping expression distributions between normal and DS samples. We hypothesize that, in each cell type, group A genes are the most dosage sensitive and are most likely involved in the constant DS traits, group B genes might be involved in variable DS traits, and group C genes are not dosage sensitive and are least likely to participate in DS pathological phenotypes. This study provides the first extensive data set on HSA21 gene-expression variation in DS and underscores its role in modulating the outcome of gene-dosage imbalance.
The American Journal of Human Genetics 09/2007; 81(2):252-63. · 10.60 Impact Factor
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ABSTRACT: A 2.8-Mb 4p16.3 terminal deletion, with proximal breakpoint at locus D4S182, was diagnosed by FISH in a 16-year-old boy who presented with a typical Wolf-Hirschhorn syndrome (WHS) phenotype. The deletion, which was maternally derived, was isolated, and a balanced translocation was ruled out in both parents by FISH with probe 33c6 (locus D4S43) falling within the patient's deletion interval, at a distance of about 2.3 Mb from the telomere. His older brother, who died from pneumonia at the age of 18 years, also presented with clinical signs consistent with WHS, including typical facial appearance and major malformations, but the genetic test was not performed. A smaller 4p deletion, spanning the 1.5 Mb region from locus D4S96 to the telomere was detected in the healthy mother. When critically analyzed, after the FISH results, she was noted to present with partial WHS facial "gestalt," borderline mental delay, a few episodes of seizures as a child, normal weight and head circumference, and height at the lower limit of normal range. This report highlights a previously undescribed mechanism of familial recurrence of a microdeletion syndrome. Potential meiotic amplification is to be considered for different subtelomeric deletions that are currently interpreted as population polymorphisms. At the same time, the present report adds new insights to mapping some peculiar WHS clinical signs, such as seizures and severe growth delay.
American Journal of Medical Genetics Part A 07/2007; 143A(11):1169-73. · 2.39 Impact Factor
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ABSTRACT: Acquired mutations activating Janus kinase 3 (jak3) have been reported in Down syndrome (DS) and non-DS patients with acute megakaryoblastic leukaemia (AMKL). This highlighted jak3-activation as an important event in the pathogenesis of AMKL, and predicted inhibitors of jak3 as conceptual therapeutics for AMKL. Of 16 DS-transient myeloproliferative disorder (TMD)/AMKL patients tested, seven showed JAK3 mutations. Three mutations deleted the kinase (JH1) domain, abolishing the main function of jak3. Another patient displayed a mutation identical to a previously reported inherited loss-of-function causing severe combined immunodeficiency. Our data suggest that both gain-, and loss-of function mutations of jak3 can be acquired in DS-TMD/AMKL.
British Journal of Haematology 06/2007; 137(4):337-41. · 4.94 Impact Factor
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Rosa Bacchetta,
Laura Passerini,
Eleonora Gambineri,
Minyue Dai,
Sarah E Allan,
Lucia Perroni, Franca Dagna-Bricarelli,
Claudia Sartirana,
Susanne Matthes-Martin,
Anita Lawitschka,
Chiara Azzari,
Steven F Ziegler,
Megan K Levings,
Maria Grazia Roncarolo
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ABSTRACT: The autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is caused by mutations in the forkhead box protein P3 (FOXP3) gene. In the mouse model of FOXP3 deficiency, the lack of CD4+ CD25+ Tregs is responsible for lethal autoimmunity, indicating that FOXP3 is required for the differentiation of this Treg subset. We show that the number and phenotype of CD4+ CD25+ T cells from IPEX patients are comparable to those of normal donors. CD4+ CD25high T cells from IPEX patients who express FOXP3 protein suppressed the in vitro proliferation of effector T cells from normal donors, when activated by "weak" TCR stimuli. In contrast, the suppressive function of CD4+ CD25high T cells from IPEX patients who do not express FOXP3 protein was profoundly impaired. Importantly, CD4+ CD25high T cells from either FOXP3+ or FOXP3- IPEX patients showed altered suppression toward autologous effector T cells. Interestingly, IL-2 and IFN-gamma production by PBMCs from IPEX patients was significantly decreased. These findings indicate that FOXP3 mutations in IPEX patients result in heterogeneous biological abnormalities, leading not necessarily to a lack of differentiation of CD4+ CD25high Tregs but rather to a dysfunction in these cells and in effector T cells.
Journal of Clinical Investigation 07/2006; 116(6):1713-22. · 15.39 Impact Factor
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Elena Gennaro,
Filippo M Santorelli,
Enrico Bertini,
Daniela Buti,
Roberto Gaggero,
Giuseppe Gobbi,
Marcella Lini,
Tiziana Granata,
Elena Freri,
Antonia Parmeggiani,
Pasquale Striano,
Pierangelo Veggiotti,
Simona Cardinali, Franca Dagna Bricarelli,
Carlo Minetti,
Federico Zara
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ABSTRACT: Severe Myoclonic Epilepsy in Infancy (SMEI) is an intractable epileptic syndrome with onset in the first year of life and is commonly caused by de novo mutations in the SCN1A gene, encoding the alpha1-subunit of the neuronal voltage-gated sodium channel. We report two unrelated families in which probands were affected by SMEI and their parents showed a single febrile seizure during early childhood or no neurological symptoms. Semiquantitative analysis of SCN1A mutations allowed the detection of a somatic and germline mosaicism in one of the parents. The study provides the first example of parental mosaicisms in SMEI and opens a new insight into the phenotypic variability and complex inheritance of this condition. The identification of germline mosaicisms has important consequences in genetic counseling of SMEI when SCN1A mutations appear to occur de novo with standard screening methods.
Biochemical and Biophysical Research Communications 04/2006; 341(2):489-93. · 2.48 Impact Factor
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Blood 10/2005; 106(5):1887-8. · 9.90 Impact Factor
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Suzanne McElwaine,
Claire Mulligan,
Jürgen Groet,
Monica Spinelli,
Andrea Rinaldi,
Gareth Denyer,
Afua Mensah,
Simona Cavani,
Chiara Baldo, Franca Dagna-Bricarelli,
Ian Hann,
Giuseppe Basso,
Finbarr E Cotter,
Dean Nizetic
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ABSTRACT: Transient myeloproliferative disorder (TMD) is a unique, spontaneously regressing neoplasia specific to Down's syndrome (DS), affecting up to 10% of DS neonates. In 20-30% of cases, it reoccurs as progressive acute megakaryoblastic leukaemia (AMKL) at 2-4 years of age. The TMD and AMKL blasts are morphologically and immuno-phenotypically identical, and have the same acquired mutations in GATA1. We performed transcript profiling of nine TMD patients comparing them with seven AMKL patients using Affymetrix HG-U133A microarrays. Similar overall transcript profiles were observed between the two conditions, which were only separable by supervised clustering. Taqman analysis on 10 TMD and 10 AMKL RNA samples verified the expression of selected differing genes, with statistical significance (P < 0.05) by Student's t-test. The Taqman differences were also reproduced on TMD and AMKL blasts sorted by a fluorescence-activated cell sorter. Among the significant differences, CDKN2C, the effector of GATA1-mediated cell cycle arrest, was increased in AMKL but not TMD, despite the similar level of GATA1. In contrast, MYCN (neuroblastoma-derived oncogene) was expressed in TMD at a significantly greater level than in AMKL. MYCN has not previously been described in leukaemogenesis. Finally, the tumour antigen PRAME was identified as a specific marker for AMKL blasts, with no expression in TMD. This study provides markers discriminating TMD from AMKL-M7 in DS. These markers have the potential as predictive, diagnostic and therapeutic targets. In addition, the study provides further clues into the pathomechanisms discerning self-regressive from the progressive phenotype.
British Journal of Haematology 06/2004; 125(6):729-42. · 4.94 Impact Factor
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Domenica Taruscio,
Vincenzo Falbo,
Giovanna Floridia,
Marco Salvatore,
Chiara Pescucci,
Alfredo Cantafora,
Cesarina Marongiu,
Anna Baroncini,
Elisa Calzolari,
Antonio Cao,
Giuseppe Castaldo, Franca Dagna Bricarelli,
Ginevra Guanti,
Lucio Nitsch,
Pier Franco Pignatti,
Cristina Rosatelli,
Francesco Salvatore,
Orsetta Zuffardi
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ABSTRACT: The first Italian national trial of external quality assessment in genetic testing was organised within the framework of the "Italian National Project for Standardisation and Quality Assurance of Genetic Tests". Sixty-eight Public Health Service laboratories volunteered for the trial, which involved molecular genetic tests (cystic fibrosis, beta-thalassaemia, familial adenomatous polyposis coli and fragile-X syndrome) and cytogenetic tests (prenatal and postnatal, the latter included cancer cytogenetics). The response rate was high (88.2%). The level of analytical accuracy was good, i.e., the percentage of laboratories that correctly genotyped all samples was 89.3% for cystic fibrosis, 90.9% for beta-thalassaemia, 100% for familial adenomatous polyposis coli (despite two laboratories did not complete the analysis because the amount of DNA was considered insufficient), and 90.5% for fragile-X syndrome. Written reports differed widely and were judged "inadequate" in over 50% of cases. Most laboratories from the present study already have experience in previous European external quality assessments for at least one genetic test; this can explain the higher analytical accuracy in the Italian external quality assessment with respect to quality control programmes in other countries. Collaborative networks are strongly suggested to improve the quality of the reports.
Clinical Chemistry and Laboratory Medicine 02/2004; 42(8):915-21. · 2.15 Impact Factor
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Jürgen Groet,
Suzanne McElwaine,
Monica Spinelli,
Andrea Rinaldi,
Ingo Burtscher,
Claire Mulligan,
Afua Mensah,
Simona Cavani, Franca Dagna-Bricarelli,
Giuseppe Basso,
Finbarr E Cotter,
Dean Nizetic
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ABSTRACT: Transient myeloid disorder is a unique self-regressing neoplasia specific to Down's syndrome. The transcription factor GATA1 is needed for normal growth and maturation of erythroid cells and megakaryocytes. Mutations in GATA1 have been reported in acute megakaryoblastic leukaemia in Down's syndrome. We aimed to investigate changes in GATA1 in patients with Down's syndrome and either transient myeloid disorder (n=10) or acute megakaryoblastic leukaemia (n=6). We recorded mutations eliminating exon 2 from GATA1 in all patients with transient myeloid disorder (age 0-24 days) and in all with acute megakaryoblastic leukaemia (age 14-38 months). The range of mutations did not differ between patients with each disorder. Patients with transient myeloid disorder with mutations in GATA1 can regress spontaneously to complete remission, and mutations do not necessarily predict later acute megakaryoblastic leukaemia.
The Lancet 06/2003; 361(9369):1617-20. · 38.28 Impact Factor
