Andrea Riccio

Publications (29)212.25 Total impact

• Article: Genetic and epigenetic mutations affect the DNA binding capability of human ZFP57 in transient neonatal diabetes type 1.

  Ilaria Baglivo, Sabrina Esposito, Lucia De Cesare, Angela Sparago, Zahra Anvar, Vincenzo Riso, Marco Cammisa, Roberto Fattorusso, Giovanna Grimaldi, Andrea Riccio, Paolo V Pedone
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  ABSTRACT: In the mouse, ZFP57 contains three classical Cys2His2 zinc finger domains (ZF) and recognizes the methylated TGC(met)CGC target sequence using the first and the second ZFs. In this study, we demonstrate that the human ZFP57 (hZFP57) containing six Cys2His2 ZFs, binds the same methylated sequence through the third and the fourth ZFs, and identify the aminoacids critical for DNA interaction. In addition, we present evidences indicating that hZFP57 mutations and hypomethylation of the TNDM1 ICR both associated with Transient Neonatal Diabetes Mellitus type 1 result in loss of hZFP57 binding to the TNDM1 locus, likely causing PLAGL1 activation.
  FEBS letters 03/2013; · 3.54 Impact Factor
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  Available from: Zahra Anvar

  Dataset: Genetic and epigenetic mutations affect the DNA binding capability 4 of human ZFP57 in transient neonatal diabetes type 1

  Ilaria Baglivo, Sabrina Esposito, Lucia De, C Q1 Esare, Angela Sparago, Zahra Anvar, Vincenzo Riso, Marco Cammisa, Roberto Fattorusso, Giovanna Grimaldi, Andrea Riccio, Paolo V Pedone
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  ABSTRACT: a b s t r a c t 30 In the mouse, ZFP57 contains three classical Cys 2 His 2 zinc finger domains (ZF) and recognizes the 31 methylated TGC met CGC target sequence using the first and the second ZFs. In this study, we demon-32 strate that the human ZFP57 (hZFP57) containing six Cys 2 His 2 ZFs, binds the same methylated 33 sequence through the third and the fourth ZFs, and identify the aminoacids critical for DNA inter-34 action. In addition, we present evidences indicating that hZFP57 mutations and hypomethylation 35 of the TNDM1 ICR both associated with Transient Neonatal Diabetes Mellitus type 1 result in loss 36 of hZFP57 binding to the TNDM1 locus, likely causing PLAGL1 activation.
• Article: Paternal deletion of the 11p15.5 centromeric-imprinting control region is associated with alteration of imprinted gene expression and recurrent severe intrauterine growth restriction.

  Agostina De Crescenzo, Angela Sparago, Flavia Cerrato, Orazio Palumbo, Massimo Carella, Marco Miceli, Moshe Bronshtein, Andrea Riccio, Yuval Yaron
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  ABSTRACT: BACKGROUND: Heterogeneous molecular defects affecting the 11p15.5 imprinted gene cluster are associated with the opposite growth disorders Beckwith-Wiedemann Syndrome (BWS) and Silver Russell syndrome (SRS). Maternal deletions of the centromeric domain usually result in BWS, but paternal deletions have been so far associated with normal phenotype. Here we describe a case of recurrent severe Intra-Uterine Growth Restriction (IUGR) with paternal transmission of an 11p15.5 60 kb deletion. METHODS AND RESULTS: Chromosome microarray (CMA), PCR and DNA sequencing analyses showed that two fetuses conceived by a normal couple inherited from their father a 60 kb deletion encompassing the Imprinting Control Region of the 11p15.5 centromeric domain. The two fetuses died in utero with severe growth restriction. PCR amplification of parental DNAs indicated that the father carried the mutation in the mosaic state. DNA methylation and gene expression analyses showed that the deletion led to an imprinting alteration restricted to the centromeric domain and resulting in silencing of KCNQ1OT1 and activation of CDKN1C and PHLDA2. CONCLUSIONS: Our data demonstrate that the phenotype associated with 11p15.5 deletions is strongly influenced by the size of the region involved and indicate imprinting defects leading to CDKN1C and PHLDA2 activation as cause of severe IUGR.
  Journal of Medical Genetics 12/2012; · 6.36 Impact Factor
• Article: The molecular function and clinical phenotype of partial deletions of the IGF2/H19 imprinting control region depends on the spatial arrangement of the remaining CTCF binding sites.

  Jasmin Beygo, Valentina Citro, Angela Sparago, Agostina De Crescenzo, Flavia Cerrato, Melanie Heitmann, Katrin Rademacher, Andrea Guala, Thorsten Enklaar, Cecilia Anichini, Margherita Cirillo Silengo, Notker Graf, Dirk Prawitt, Maria Vittoria Cubellis, Bernhard Horstemke, Karin Buiting, Andrea Riccio
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  ABSTRACT: At chromosome 11p15.5, the Imprinting Centre 1 (IC1) controls the parent of origin-specific expression of the IGF2 and H19 genes. The 5 kb IC1 region contains multiple target sites (CTS) for the zinc-finger protein CTCF, whose binding on the maternal chromosome prevents the activation of IGF2 and allows that of H19 by common enhancers. CTCF binding helps maintaining the maternal IC1 methylation-free, whereas on the paternal chromosome gamete-inherited DNA methylation inhibits CTCF interaction and enhancer-blocking activity resulting in IGF2 activation and H19 silencing. Maternally inherited 1.4-2.2 kb deletions are associated with methylation of the residual CTSs and Beckwith-Wiedemann Syndrome (BWS), although with different penetrance and expressivity. We explored the relationship between IC1 microdeletions and phenotype by analysing a number of previously described and novel mutant alleles. We used a highly quantitative assay based on next generation sequencing to measure DNA methylation in affected families and analysed enhancer-blocking activity and CTCF binding in cultured cells. We demonstrate that the microdeletions mostly affect IC1 function and CTCF binding by changing CTS spacing. Thus, the extent of IC1 inactivation and the clinical phenotype are influenced by the arrangement of the residual CTSs. A CTS spacing similar to the wildtype allele results in moderate IC1 inactivation and is associated with stochastic DNA methylation of the maternal IC1 and incomplete penetrance. Microdeletions with different CTS spacing display severe IC1 inactivation and are associated with IC1 hypermethylation and complete penetrance. Careful characterization of the IC1 microdeletions is therefore needed to predict recurrence risks and phenotypical outcomes.
  Human Molecular Genetics 10/2012; · 7.64 Impact Factor
• Article: Nephrological findings and genotype-phenotype correlation in Beckwith-Wiedemann syndrome.

  Alessandro Mussa, Licia Peruzzi, Nicoletta Chiesa, Agostina De Crescenzo, Silvia Russo, Daniela Melis, Luigi Tarani, Giuseppina Baldassarre, Lidia Larizza, Andrea Riccio, Margherita Silengo, Giovanni Battista Ferrero
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  ABSTRACT: Beckwith-Wiedemann syndrome (BWS), an overgrowth disorder with several congenital abnormalities, encompasses nephrourological anomalies. The objective of the report is to analyze the latter and related genotype-phenotype correlations. The study was a retrospective review of nephrourological investigations and genotype in 67 BWS patients. Imaging and laboratory studies have been correlated with the molecular anomalies typical of BWS. Thirty-eight (56.7%) patients had a total of 61 nonmalignant nephrourological findings, including nephromegaly (n = 24), collecting system abnormalities (n = 14), cryptorchidism (n = 11), nephrolithiasis (n = 5), cysts (n = 5), and dysplasia (n = 1). Four patients had Wilms' tumor, all associated with renal hyperplasia. Renal findings were almost consistent in the BWS(IC1) group, with nephromegaly in all patients and collecting system abnormalities in half of them. BWS(UPD) and negative patients also had frequent anomalies (63.6% and 61.9% respectively), whereas only 36.0% of BWS(IC2) had renal findings (p = 0.003). Cryptorchidism was associated with abdominal wall defects (p < 0.001) appearing more frequently in BWS(IC2) (p = 0.028). Urinary tract infections were observed in 17.9% of patients, with two resulting in life-threatening sepsis. Hypercalciuria was present in 10% of cases. 55.5% of BWS patients have renal findings. Although variegate, these anomalies disclose a genotype-phenotype correlation.
  Pediatric Nephrology 03/2012; 27(3):397-406. · 2.52 Impact Factor
• Article: Gain of function in CDKN1C.

  Andrea Riccio, Maria Vittoria Cubellis
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  ABSTRACT: Loss-of-function mutations in the gene encoding the cyclin-dependent kinase inhibitor CDKN1C cause Beckwith-Wiedemann syndrome and cancer. A new study now identifies potentially gain-of-function missense mutations in CDKN1C that cause the undergrowth-associated IMAGe syndrome.
  Nature Genetics 01/2012; 44(7):737-8. · 35.53 Impact Factor
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  Available from: Simon Quenneville

  Article: In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions.

  Simon Quenneville, Gaetano Verde, Andrea Corsinotti, Adamandia Kapopoulou, Johan Jakobsson, Sandra Offner, Ilaria Baglivo, Paolo V Pedone, Giovanna Grimaldi, Andrea Riccio, Didier Trono
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  ABSTRACT: The maintenance of H3K9 and DNA methylation at imprinting control regions (ICRs) during early embryogenesis is key to the regulation of imprinted genes. Here, we reveal that ZFP57, its cofactor KAP1, and associated effectors bind selectively to the H3K9me3-bearing, DNA-methylated allele of ICRs in ES cells. KAP1 deletion induces a loss of heterochromatin marks at ICRs, whereas deleting ZFP57 or DNMTs leads to ICR DNA demethylation. Accordingly, we find that ZFP57 and KAP1 associated with DNMTs and hemimethylated DNA-binding NP95. Finally, we identify the methylated TGCCGC hexanucleotide as the motif that is recognized by ZFP57 in all ICRs and in several tens of additional loci, several of which are at least ZFP57-dependently methylated in ES cells. These results significantly advance our understanding of imprinting and suggest a general mechanism for the protection of specific loci against the wave of DNA demethylation that affects the mammalian genome during early embryogenesis.
  Molecular cell 11/2011; 44(3):361-72. · 14.61 Impact Factor
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  Available from: Massimo Carella

  Article: The KCNQ1OT1 imprinting control region and non-coding RNA: new properties derived from the study of Beckwith-Wiedemann syndrome and Silver-Russell syndrome cases.

  Nicoletta Chiesa, Agostina De Crescenzo, Kankadeb Mishra, Lucia Perone, Massimo Carella, Orazio Palumbo, Alessandro Mussa, Angela Sparago, Flavia Cerrato, Silvia Russo, Elisabetta Lapi, Maria Vittoria Cubellis, Chandrasekhar Kanduri, Margherita Cirillo Silengo, Andrea Riccio, Giovanni Battista Ferrero
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  ABSTRACT: A cluster of imprinted genes at chromosome 11p15.5 is associated with the growth disorders, Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS). The cluster is divided into two domains with independent imprinting control regions (ICRs). We describe two maternal 11p15.5 microduplications with contrasting phenotypes. The first is an inverted and in cis duplication of the entire 11p15.5 cluster associated with the maintenance of genomic imprinting and with the SRS phenotype. The second is a 160 kb duplication also inverted and in cis, but resulting in the imprinting alteration of the centromeric domain. It includes the centromeric ICR (ICR2) and the most 5' 20 kb of the non-coding KCNQ1OT1 gene. Its maternal transmission is associated with ICR2 hypomethylation and the BWS phenotype. By excluding epigenetic mosaicism, cell clones analysis indicated that the two closely located ICR2 sequences resulting from the 160 kb duplication carried discordant DNA methylation on the maternal chromosome and supported the hypothesis that the ICR2 sequence is not sufficient for establishing imprinted methylation and some other property, possibly orientation-dependent, is needed. Furthermore, the 1.2 Mb duplication demonstrated that all features are present for correct imprinting at ICR2 when this is duplicated and inverted within the entire cluster. In the individuals maternally inheriting the 160 kb duplication, ICR2 hypomethylation led to the expression of a truncated KCNQ1OT1 transcript and to down-regulation of CDKN1C. We demonstrated by chromatin RNA immunopurification that the KCNQ1OT1 RNA interacts with chromatin through its most 5' 20 kb sequence, providing a mechanism likely mediating the silencing activity of this long non-coding RNA.
  Human Molecular Genetics 09/2011; 21(1):10-25. · 7.64 Impact Factor
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  Available from: PubMed Central

  Article: A novel microdeletion in the IGF2/H19 imprinting centre region defines a recurrent mutation mechanism in familial Beckwith-Wiedemann syndrome.

  Agostina De Crescenzo, Filomena Coppola, Pietro Falco, Italo Bernardo, Gaetano Ausanio, Flavia Cerrato, Luigi Falco, Andrea Riccio
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  ABSTRACT: The overgrowth disorder Beckwith-Wiedemann syndrome (BWS) is associated with dysregulation of imprinted genes at chromosome 11p15.5. The molecular defects are heterogeneous but most of the cases are associated with defective DNA methylation at either one of two Imprinting Control Regions (IC1 and IC2) or Uniparental paternal Disomy (UPD) at 11p15.5. In rare cases, the BWS phenotype has been found associated with maternal transmission of IC1 microdeletions. We describe a family with a novel 1.8 kb deletion that is associated with hypermethylation at IC1. The mutation results from recombination between highly homologous sequences containing target sites for the zinc-finger protein CTCF (CTSs). This finding supports the hypothesis that the function of IC1 and the penetrance of the clinical phenotype depend on the spacing of the CTSs resulting from recombination in the mutant allele.
  European journal of medical genetics 05/2011; 54(4):e451-4. · 1.57 Impact Factor
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  Available from: Adele Murrell

  Article: Disruption of genomic neighbourhood at the imprinted IGF2-H19 locus in Beckwith-Wiedemann syndrome and Silver-Russell syndrome.

  Raffaella Nativio, Angela Sparago, Yoko Ito, Rosanna Weksberg, Andrea Riccio, Adele Murrell
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  ABSTRACT: Hyper- and hypomethylation at the IGF2-H19 imprinting control region (ICR) result in reciprocal changes in IGF2-H19 expression and the two contrasting growth disorders, Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). DNA methylation of the ICR controls the reciprocal imprinting of IGF2 and H19 by preventing the binding of the insulator protein, CTCF. We here show that local changes in histone modifications and CTCF--cohesin binding at the ICR in BWS and SRS together with DNA methylation correlate with the higher order chromatin structure at the locus. In lymphoblastoid cells from control individuals, we found the repressive histone H3K9me3 and H4K20me3 marks associated with the methylated paternal ICR allele and the bivalent H3K4me2/H3K27me3 mark together with H3K9ac and CTCF--cohesin associated with the non-methylated maternal allele. In patient-derived cell lines, the mat/pat asymmetric distribution of these epigenetic marks was lost with H3K9me3 and H4K20me3 becoming biallelic in the BWS and H3K4me2, H3K27me3 and H3K9ac together with CTCF-cohesin becoming biallelic in the SRS. We further show that in BWS and SRS cells, there is opposing chromatin looping conformation mediated by CTCF--cohesin binding sites surrounding the locus. In normal cells, lack of CTCF--cohesin binding at the paternal ICR is associated with monoallelic interaction between two CTCF sites flanking the locus. CTCF--cohesin binding at the maternal ICR blocks this interaction by associating with the CTCF site downstream of the enhancers. The two alternative chromatin conformations are differently favoured in BWS and SRS likely predisposing the locus to the activation of IGF2 or H19, respectively.
  Human Molecular Genetics 02/2011; 20(7):1363-74. · 7.64 Impact Factor
• Article: Silver-Russell syndrome and Beckwith-Wiedemann syndrome phenotypes associated with 11p duplication in a single family.

  Laura Cardarelli, Angela Sparago, Agostina De Crescenzo, Elisa Nalesso, Barbara Zavan, Maria Vittoria Cubellis, Angelo Selicorni, Paola Cavicchioli, Giovanni Battista Pozzan, Marilena Petrella, Andrea Riccio
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  ABSTRACT: Genomic imprinting is an epigenetic phenomenon resulting in differential expression of maternal and paternal alleles of a subset of genes. In the mouse, mutation of imprinted genes often results in contrasting phenotypes, depending on parental origin. The overgrowth-associated Beckwith-Wiedemann syndrome (BWS) and the growth restriction-associated Silver-Russell syndrome (SRS) have been linked with a variety of epigenetic and genetic defects affecting a cluster of imprinted genes at chromosome 11p15.5. Paternally derived and maternally derived 11p15.5 duplications represent infrequent findings in BWS and SRS, respectively. Here, we report a case in which a 6.5 Mb duplication of 11p15.4-pter resulted in SRS and BWS phenotypes in a child and her mother, respectively. Molecular analyses demonstrated that the duplication involved the maternal chromosome 11p15 in the child and the paternal chromosome 11p15 in the mother. This observation provides a direct demonstration that SRS and BWS represent specular images, both at the clinical and molecular levels.
  Pediatric and Developmental Pathology 12/2009; 13(4):326-30. · 0.99 Impact Factor
• Article: A case of Beckwith-Wiedemann syndrome caused by a cryptic 11p15 deletion encompassing the centromeric imprinted domain of the BWS locus.

  Marcella Zollino, Daniela Orteschi, Giuseppe Marangi, Agostina De Crescenzo, Vanna Pecile, Andrea Riccio, Giovanni Neri
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  ABSTRACT: BACKGROUND Beckwith-Wiedemann syndrome (BWS) is a clinically variable and genetically heterogeneous disorder, providing evidence that imprinted genes play key roles in the control of fetal growth. Clinically, diagnostic criteria include macrosomia, macroglossia, abdominal wall defects, neonatal hypoglycaemia, visceromegalies and hemihyperplasia. Component clinical manifestations also include renal abnormalities, adrenocortical cytomegaly and a characteristic facial appearance, with midface hypoplasia and ear anomalies. Genetically, BWS is associated with disturbances within two different domains on 11p15 that are controlled by distinct imprinting control regions (ICR), ICR1 and ICR2. The majority of patients have abnormalities within ICR2. In particular, loss of maternal methylation accounts for 50-60% of cases, and is associated with reduction in the expression of the CDKN1C gene, a member of the cyclin dependent kinase inhibitor family acting as negative regulator of cell proliferation. Mutations in CDKN1C are detected in another 5-10% of subjects with sporadic BWS. Chromosome deletions affecting ICR2 are uncommon. METHODS AND FINDINGS We report on a patient with BWS in which a de novo 11p15 deletion was detected by array comparative genomic hybridisation. Clinically, the patient presented with mild mental retardation and minor physical anomalies. The deletion, that was demonstrated to be maternal in origin by SNP array, encompassed ICR2 and several flanking genes, including CDKN1C. A normal methylation pattern of ICR1 was observed. CONCLUSIONS This observation provides evidence that, among the genetic defects associated with BWS, a 11p15 microdeletion encompassing ICR2 identifies a peculiar clinical phenotype, with high recurrence risk in offspring of female carriers. It also supports the model of two independent domains within the BWS locus.
  Journal of Medical Genetics 10/2009; 47(6):429-32. · 6.36 Impact Factor
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  Available from: Gaetano Verde

  Article: Inherited and Sporadic Epimutations at the IGF2-H19 locus in Beckwith-Wiedemann syndrome and Wilms' tumor.

  Andrea Riccio, Angela Sparago, Gaetano Verde, Agostina De Crescenzo, Valentina Citro, Maria Vittoria Cubellis, Giovanni Battista Ferrero, Margherita Cirillo Silengo, Silvia Russo, Lidia Larizza, Flavia Cerrato
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  ABSTRACT: The parent-of-origin-dependent expression of IGF2 and H19 is controlled by the imprinting center 1 (IC1) consisting of a methylation-sensitive chromatin insulator. IC1 is normally methylated on the paternal chromosome and nonmethylated on the maternal chromosome. We found that 22 cases in a large cohort of patients affected by Beckwith-Wiedemann syndrome (BWS) had IC1 methylated on both parental chromosomes, resulting in biallelic activation of IGF2 and biallelic silencing of H19. These individuals had marked macrosomia and high incidence of Wilms' tumor. A subset of these patients had 1.4- to 1.8-kb deletions with hypermethylation of the remaining IC1 region and fully penetrant BWS phenotype when transmitted maternally. Another subset of individuals with IC1 hypermethylation had a similar clinical phenotype but no mutation in the local vicinity. All these cases were sporadic and in at least two families affected and unaffected members shared the same maternal IC1 allele but not the abnormal maternal epigenotype. Similarly, no IC1 deletion was detected in 10 nonsyndromic Wilms' tumors with IC1 hypermethylation. In conclusion, methylation defects at the IGF2-H19 locus can result from inherited mutations of the imprinting center and have high recurrence risk or arise independently from the sequence context and not transmitted to the progeny.
  Endocrine development 02/2009; 14:1-9.
• Article: Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome.

  Jet Bliek, Gaetano Verde, Jonathan Callaway, Saskia M Maas, Agostina De Crescenzo, Angela Sparago, Flavia Cerrato, Silvia Russo, Serena Ferraiuolo, Maria Michela Rinaldi, Rita Fischetto, Faustina Lalatta, Lucio Giordano, Paola Ferrari, Maria Vittoria Cubellis, Lidia Larizza, I Karen Temple, Marcel M A M Mannens, Deborah J G Mackay, Andrea Riccio
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  ABSTRACT: Genomic imprinting is an epigenetic phenomenon restricting gene expression in a manner dependent on parent of origin. Imprinted gene products are critical regulators of growth and development, and imprinting disorders are associated with both genetic and epigenetic mutations, including disruption of DNA methylation within the imprinting control regions (ICRs) of these genes. It was recently reported that some patients with imprinting disorders have a more generalised imprinting defect, with hypomethylation at a range of maternally methylated ICRs. We report a cohort of 149 patients with a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS), including 81 with maternal hypomethylation of the KCNQ1OT1 ICR. Methylation analysis of 11 ICRs in these patients showed that hypomethylation affecting multiple imprinted loci was restricted to 17 patients with hypomethylation of the KCNQ1OT1 ICR, and involved only maternally methylated loci. Both partial and complete hypomethylation was demonstrated in these cases, suggesting a possible postzygotic origin of a mosaic imprinting error. Some ICRs, including the PLAGL1 and GNAS/NESPAS ICRs implicated in the aetiology of transient neonatal diabetes and pseudohypoparathyroidism type 1b, respectively, were more frequently affected than others. Although we did not find any evidence for mutation of the candidate gene DNMT3L, these results support the hypotheses that trans-acting factors affect the somatic maintenance of imprinting at multiple maternally methylated loci and that the clinical presentation of these complex cases may reflect the loci and tissues affected with the epigenetic abnormalities.
  European journal of human genetics: EJHG 01/2009; 17(5):611-9. · 3.56 Impact Factor
• Article: High frequency of loss of heterozygosity at 11p15 and IGF2 overexpression are not related to clinical outcome in childhood adrenocortical tumors positive for the R337H TP53 mutation.

  Roberto Rosati, Flavia Cerrato, Mabrouka Doghman, Mara A D Pianovski, Guilherme A Parise, Gislaine Custódio, Gerard P Zambetti, Raul C Ribeiro, Andrea Riccio, Bonald C Figueiredo, Enzo Lalli
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  ABSTRACT: A germline TP53 R337H mutation is present in childhood adrenocortical tumors (ACT) from southern Brazil. Other genetic alterations are also frequently found in these tumors. This study was designed to assess whether alterations of the 11p15 region exist in childhood ACT, accounting for IGF2 overexpression in these tumors, and how they are related to clinical outcome. Tumor DNA of 12 children with ACT (4 adenomas and 8 carcinomas) and from the blood of their parents was analyzed. All patients showed 11p15 loss of heterozygosity (LOH) in the tumor. In contrast to the single case of paternal LOH, IGF2 was overexpressed in tumors with maternal allele loss. Our data show that 11p15 LOH is a widespread finding in childhood ACT not related with malignancy, contrary to adult ACT. Alterations in the expression of other genes in the same region (e.g., CDKN1C) may contribute to ACT tumorigenesis.
  Cancer genetics and cytogenetics 11/2008; 186(1):19-24. · 1.54 Impact Factor
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  Available from: pnas.org

  Article: The H19 locus acts in vivo as a tumor suppressor.

  Tomomi Yoshimizu, Audrey Miroglio, Marie-Anne Ripoche, Anne Gabory, Maria Vernucci, Andrea Riccio, Sabine Colnot, Cécile Godard, Benoit Terris, Hélène Jammes, Luisa Dandolo
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  ABSTRACT: The H19 locus belongs to a cluster of imprinted genes that is linked to the human Beckwith-Wiedemann syndrome. The expression of H19 and its closely associated IGF2 gene is frequently deregulated in some human tumors, such as Wilms' tumors. In these cases, biallelic IGF2 expression and lack of expression of H19 are associated with hypermethylation of the imprinting center of this locus. These observations and others have suggested a potential tumor suppressor effect of the H19 locus. Some studies have also suggested that H19 is an oncogene, based on tissue culture systems. We show, using in vivo murine models of tumorigenesis, that the H19 locus controls the size of experimental teratocarcinomas, the number of polyps in the Apc murine model of colorectal cancer and the timing of appearance of SV40-induced hepatocarcinomas. The H19 locus thus clearly displays a tumor suppressor effect in mice.
  Proceedings of the National Academy of Sciences 09/2008; 105(34):12417-22. · 9.68 Impact Factor
• Article: Silver-Russell syndrome following in vitro fertilization.

  Sofia Douzgou, Rita Mingarelli, Luigi Tarani, Agostina De Crescenzo, Andrea Riccio
  Pediatric and Developmental Pathology 06/2008; 11(4):329-31. · 0.99 Impact Factor
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  Available from: Gaetano Verde

  Article: Different mechanisms cause imprinting defects at the IGF2/H19 locus in Beckwith-Wiedemann syndrome and Wilms' tumour.

  Flavia Cerrato, Angela Sparago, Gaetano Verde, Agostina De Crescenzo, Valentina Citro, Maria Vittoria Cubellis, Maria Michela Rinaldi, Luigi Boccuto, Giovanni Neri, Cinzia Magnani, Paolo D'Angelo, Paola Collini, Daniela Perotti, Gianfranco Sebastio, Eamonn R Maher, Andrea Riccio
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  ABSTRACT: The parent of origin-dependent expression of the IGF2 and H19 genes is controlled by the imprinting centre 1 (IC1) consisting in a methylation-sensitive chromatin insulator. Deletions removing part of IC1 have been found in patients affected by the overgrowth- and tumour-associated Beckwith-Wiedemann syndrome (BWS). These mutations result in the hypermethylation of the remaining IC1 region, loss of IGF2/H19 imprinting and fully penetrant BWS phenotype when maternally transmitted. We now report that 12 additional cases with IC1 hypermethylation have a similar clinical phenotype but showed neither a detectable deletion nor other mutation in the local vicinity. Likewise, no IC1 deletion was detected in 40 sporadic non-syndromic Wilms' tumours. A detailed analysis of the BWS patients showed that the hypermethylation variably affected the IC1 region and was generally mosaic. We observed that all these cases were sporadic and in at least two families affected and unaffected members shared the same maternal IC1 allele but not the abnormal maternal chromosome epigenotype. Furthermore, the chromosome with the imprinting defect derived from either the maternal grandfather or maternal grandmother. Overall, these results indicate that methylation-imprinting defects at the IGF2-H19 locus can result from inherited mutations of the IC and have high recurrence risk or arise independently from the sequence context and generally not transmitted to the progeny. Despite these differences, the epigenetic abnormalities are usually present in the patients in the mosaic form and probably acquired by post-zygotic de novo methylation. Distinguishing between these two groups of cases is important for genetic counselling.
  Human Molecular Genetics 06/2008; 17(10):1427-35. · 7.64 Impact Factor
• Article: MS-MLPA is a specific and sensitive technique for detecting all chromosome 11p15.5 imprinting defects of BWS and SRS in a single-tube experiment.

  Manuela Priolo, Angela Sparago, Corrado Mammì, Flavia Cerrato, Carmelo Laganà, Andrea Riccio
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  ABSTRACT: Human chromosome 11p15.5 harbours a large cluster of imprinted genes. Different epigenetic defects at this locus have been associated with both Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). Multiple techniques (Southern blotting, COBRA and microsatellite analysis) have been used so far to detect various DNA methylation abnormalities, uniparental disomies and copy number variations, which are characteristics of these two diseases. We have now evaluated a methylation-specific multiplex-ligation-dependent probe amplification assay (MS-MLPA) for the molecular diagnosis of BWS and SRS. Seventy-three samples derived from BWS- and SRS-affected individuals and 20 controls were analysed by conventional tests and MS-MLPA in blind. All cases that were found positive with conventional methods were also identified by MS-MLPA. These included cases with paternal UPD11, hyper- or hypo-methylation at the Imprinting Centre 1 or Imprinting Centre 2 and rare 11p15.5 duplications. In summary, this MS-MLPA assay can detect both copy number variations and methylation defects of the 11p15.5 critical region within one single experiment and represents an easy, low cost and reliable system for the molecular diagnostics of BWS and SRS.
  European Journal of HumanGenetics 06/2008; 16(5):565-71. · 4.40 Impact Factor
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  Available from: Gaetano Verde

  Article: Distinct methylation changes at the IGF2-H19 locus in congenital growth disorders and cancer.

  Adele Murrell, Yoko Ito, Gaetano Verde, Joanna Huddleston, Kathryn Woodfine, Margherita Cirillo Silengo, Filippo Spreafico, Daniela Perotti, Agostina De Crescenzo, Angela Sparago, Flavia Cerrato, Andrea Riccio
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  ABSTRACT: Differentially methylated regions (DMRs) are associated with many imprinted genes. In mice methylation at a DMR upstream of the H19 gene known as the Imprint Control region (IC1) is acquired in the male germline and influences the methylation status of DMRs 100 kb away in the adjacent Insulin-like growth factor 2 (Igf2) gene through long-range interactions. In humans, germline-derived or post-zygotically acquired imprinting defects at IC1 are associated with aberrant activation or repression of IGF2, resulting in the congenital growth disorders Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, respectively. In Wilms tumour and colorectal cancer, biallelic expression of IGF2 has been observed in association with loss of methylation at a DMR in IGF2. This DMR, known as DMR0, has been shown to be methylated on the silent maternal IGF2 allele presumably with a role in repression. The effect of IGF2 DMR0 methylation changes in the aetiology of BWS or SRS is unknown. We analysed the methylation status of the DMR0 in BWS, SRS and Wilms tumour patients by conventional bisulphite sequencing and pyrosequencing. We show here that, contrary to previous reports, the IGF2 DMR0 is actually methylated on the active paternal allele in peripheral blood and kidney. This is similar to the IC1 methylation status and is inconsistent with the proposed silencing function of the maternal IGF2 allele. Beckwith-Wiedemann and Silver-Russell patients with IC1 methylation defects have similar methylation defects at the IGF2 DMR0, consistent with IC1 regulating methylation at IGF2 in cis. In Wilms tumour, however, methylation profiles of IC1 and IGF2 DMR0 are indicative of methylation changes occurring on both parental alleles rather than in cis. These results support a model in which DMR0 and IC1 have opposite susceptibilities to global hyper and hypomethylation during tumorigenesis independent of the parent of origin imprint. In contrast, during embryogenesis DMR0 is methylated or demethylated according to the germline methylation imprint at the IC1, indicating different mechanisms of imprinting loss in neoplastic and non-neoplastic cells.
  PLoS ONE 02/2008; 3(3):e1849. · 4.09 Impact Factor