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Giuseppina Lacerra
Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, (IGB-ABT, CNR), National Research Council, 80131 Naples, Italy

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Journal article
Published: 31 July 2020 in Genes
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We identified two unstable variants in the third exon of α-globin genes: Hb Bernalda/Groene Hart (HBA1:c.358C>T), and Hb Caserta (HBA2:c.79G>A) in cis to Hb Sun Prairie (HBA2:c.391G>C), also named Hb Southern Italy. These mutations occurred in the H helix of the α-globin that is involved in heme contacting, specific recognition of α-hemoglobin-stabilizing protein (AHSP), and α1β1 interactions. The carriers showed α-thalassemia phenotype, but one also jaundice and cholelithiasis. Molecular identification of clusters of families in Southern Italy encouraged molecular characterization of mRNA, globin chain analyses, molecular modeling studies, and comparison with globin variants to understand the mechanisms causing the α-thalassemia phenotype. A normal amount of Hb Bernalda/Groene Hart mRNA were found, and molecular modeling highlighted additional H bonds with AHSP. For Hb Southern Italy, showing an unexpected α/β biosynthetic ratio typical of the β-thalassemia type, two different molecular mechanisms were shown: Reduction of the variant mRNA, likely due to the No-Go Decay for the presence of unused triplet ACG at cod 26, and protein instability due to the impairment of AHSP interaction. The UDP glucuronosyltransferase 1A (UGT1A1) genotyping was conclusive in the case of jaundice and cholelithiasis. Multiple approaches are needed to properly identify the mechanisms leading to unstable variants and the effect of a mutation.

ACS Style

Giovanna Cardiero; Gennaro Musollino; Maria Grazia Friscia; Rosario Testa; Lucrezia Virruso; Caterina Di Girgenti; Mercedes Caldora; Rosario Colella Bisogno; Carlo Gaudiano; Giuseppe Manco; Giuseppina Lacerra. Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy. Genes 2020, 11, 870 .

AMA Style

Giovanna Cardiero, Gennaro Musollino, Maria Grazia Friscia, Rosario Testa, Lucrezia Virruso, Caterina Di Girgenti, Mercedes Caldora, Rosario Colella Bisogno, Carlo Gaudiano, Giuseppe Manco, Giuseppina Lacerra. Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy. Genes. 2020; 11 (8):870.

Chicago/Turabian Style

Giovanna Cardiero; Gennaro Musollino; Maria Grazia Friscia; Rosario Testa; Lucrezia Virruso; Caterina Di Girgenti; Mercedes Caldora; Rosario Colella Bisogno; Carlo Gaudiano; Giuseppe Manco; Giuseppina Lacerra. 2020. "Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy." Genes 11, no. 8: 870.

Journal article
Published: 07 May 2020 in Cell Death & Disease
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The activity of human paraoxonase 2 (PON2) is rapidly reduced in cells incubated with the bacterial quorormone 3-Oxo-dodecanoyl Homoserine Lactone (3OC12HSL), an observation that led to hypothesize a fast PON2 post-translational modification (PTM). Recently, we detected a 3OC12HSL-induced PTM in a cell-free system in which a crude extract from 3OC12HSL-treated HeLa cells was able to inactivate and ubiquitinate at position 144 a recombinant PON2. Here we show the occurrence of this and new PTMs on PON2 in HeLa cells. PTMs were found to gather nearby the two SNPs, A148G, and S311C, that are related to type-2 diabetes and its complications. Furthermore, we detected a PTM nearby a 12 amino acids region that is deleted in PON2 Isoform 2. An in vitro mutation analysis showed that the SNPs and the deletion are involved in PON2 activity and suggested a role of PTMs on its modulation, while a SAXS analysis pointed to Isoform 2 as being largely unstructured, compared to the wild type. Besides, we discovered a control of PON2 expression via a putative mRNA operon involving the Wilms tumor 1 associated protein (WTAP) and the E3 ubiquitin ligase (E3UbL) baculoviral IAP repeat-containing 3 (BIRC3).

ACS Style

Teresa Maria Carusone; Giovanna Cardiero; Mariangela Cerreta; Luigi Mandrich; Oscar Moran; Elena Porzio; Giuliana Catara; Giuseppina Lacerra; Giuseppe Manco. WTAP and BIRC3 are involved in the posttranscriptional mechanisms that impact on the expression and activity of the human lactonase PON2. Cell Death & Disease 2020, 11, 324 -17.

AMA Style

Teresa Maria Carusone, Giovanna Cardiero, Mariangela Cerreta, Luigi Mandrich, Oscar Moran, Elena Porzio, Giuliana Catara, Giuseppina Lacerra, Giuseppe Manco. WTAP and BIRC3 are involved in the posttranscriptional mechanisms that impact on the expression and activity of the human lactonase PON2. Cell Death & Disease. 2020; 11 (5):324-17.

Chicago/Turabian Style

Teresa Maria Carusone; Giovanna Cardiero; Mariangela Cerreta; Luigi Mandrich; Oscar Moran; Elena Porzio; Giuliana Catara; Giuseppina Lacerra; Giuseppe Manco. 2020. "WTAP and BIRC3 are involved in the posttranscriptional mechanisms that impact on the expression and activity of the human lactonase PON2." Cell Death & Disease 11, no. 5: 324-17.

Journal article
Published: 01 October 2017 in The International Journal of Biochemistry & Cell Biology
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The α-thalassemia is a common disease due in prevalence to deletional mutants. We have identified two new α-thalassemia pointform mutants: α1 cod22 GGC > GGT Gly > Gly creating a 5' splicing sequence and: α1 cod23 GAG >TAG Glu > stop. We perform a qualitative and semi-quantitative analysis of the mRNA molecules, from blood of the carriers, to define the molecular mechanisms giving rise to thalassemia phenotype. In vitro analysis using minigenes and cycloheximide was performed to evaluate if the mutants are substrate of nonsense-mediated mRNA decay. In the α1 cod22 GGC > GGT the new 5' splicing site in exon 1 completely substitutes the normal one. We demonstrated the presence of a mRNA decay as the abnormally spliced mRNA was consistent in the nucleus, partially degraded in the cytoplasm of cells in culture, but only 2.8% in the reticulocytes. The analysis of the cod23 α-globin transcript showed an escape from the nonsense-mediated mRNA decay as for human β-globin transcript with nonsense mutations in the first exon: the anomalous mRNA was reduced in the nucleus, followed by only slight lowering from 32% to 27% of the normal α1 mRNA in the reticulocytes. In both the mutants we showed a moderate sensitivity to the NMD assay and we speculate the activation of other RNA surveillance mechanisms for the cod22 mutant. No activation of the cryptic splice site was detected and no role could be assigned to the Nonsense Alternative Splicing. Studies on transcripts from patient cells represents a very useful approach providing many information about the mechanisms used in vivo.

ACS Style

Giovanna Cardiero; Clelia Scarano; Gennaro Musollino; Francesca Di Noce; Romeo Prezioso; Sabrina Dembech; Gaetana La Porta; Mercedes Caldora; Maria Grazia Bisconte; Rosario Colella Bisogno; Giuseppina Lacerra. Role of nonsense-mediated decay and nonsense-associated altered splicing in the mRNA pattern of two new α-thalassemia mutants. The International Journal of Biochemistry & Cell Biology 2017, 91, 212 -222.

AMA Style

Giovanna Cardiero, Clelia Scarano, Gennaro Musollino, Francesca Di Noce, Romeo Prezioso, Sabrina Dembech, Gaetana La Porta, Mercedes Caldora, Maria Grazia Bisconte, Rosario Colella Bisogno, Giuseppina Lacerra. Role of nonsense-mediated decay and nonsense-associated altered splicing in the mRNA pattern of two new α-thalassemia mutants. The International Journal of Biochemistry & Cell Biology. 2017; 91 ():212-222.

Chicago/Turabian Style

Giovanna Cardiero; Clelia Scarano; Gennaro Musollino; Francesca Di Noce; Romeo Prezioso; Sabrina Dembech; Gaetana La Porta; Mercedes Caldora; Maria Grazia Bisconte; Rosario Colella Bisogno; Giuseppina Lacerra. 2017. "Role of nonsense-mediated decay and nonsense-associated altered splicing in the mRNA pattern of two new α-thalassemia mutants." The International Journal of Biochemistry & Cell Biology 91, no. : 212-222.

Case reports
Published: 24 February 2016 in Hematology
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To verify the presence of β-thalassemia in subjects showing hematologic phenotype of α-thalassemia, conduct normal molecular sequence analysis of the α-globin genes, and detect the absence of the most frequent α-thalassemia deletions.A patient from Apulia (Southern Italy) was referred to our institution for the occasional founding of hypochromic polyglobulia and microcytic red blood cells associated with normal levels of Hb A2 and Hb F and normal iron parameters.The patient has been investigated using Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), quantitative real-time PCR, restriction analysis, and gap-PCR. A novel deletion, the Italian (ϵγδβ)(0)-thalassemia, has been identified. The 5' breakpoint was within a LINE element of 80 kb 3' of the ε-globin gene, and the 3' breakpoint was within a 160-bp palindrome of about 30 kb 5' of the β-globin gene. The breakpoint region was characterized by the presence of a microhomology (5'-TCT-3') and of an insertion of 43 bp owing to the duplication of the 160-bp palindrome. Comparison of the Hb and Hb A2 values of (ϵγδβ)(0)-thalassemia from the literature with those of (molecularly known) thalassemia carriers indicated a higher level of Hb A2 with respect to α-thalassemia and a lower level of Hb with respect to β(0)-thalassemia carriers.In this study, we report the first (ϵγδβ)(0)-thalassemia case identified in Italy. To avoid misdiagnosis of β-thalassemia, we suggest verifying the presence of large deletions of the β-globin gene cluster in subjects showing a higher border line level of Hb A2 and a lower level of Hb.

ACS Style

Giovanna Cardiero; Romeo Prezioso; Sabrina Dembech; Francesca Del Vecchio Blanco; Clelia Scarano; Giuseppina Lacerra. Identification and molecular characterization of a novel 163 kb deletion: The Italian (ϵγδβ)0-thalassemia. Hematology 2016, 21, 317 -324.

AMA Style

Giovanna Cardiero, Romeo Prezioso, Sabrina Dembech, Francesca Del Vecchio Blanco, Clelia Scarano, Giuseppina Lacerra. Identification and molecular characterization of a novel 163 kb deletion: The Italian (ϵγδβ)0-thalassemia. Hematology. 2016; 21 (5):317-324.

Chicago/Turabian Style

Giovanna Cardiero; Romeo Prezioso; Sabrina Dembech; Francesca Del Vecchio Blanco; Clelia Scarano; Giuseppina Lacerra. 2016. "Identification and molecular characterization of a novel 163 kb deletion: The Italian (ϵγδβ)0-thalassemia." Hematology 21, no. 5: 317-324.

Case reports
Published: 02 March 2015 in PLOS ONE
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We identified two new variants in the third exon of the α-globin gene in families from southern Italy: the Hb Rogliano, α1 cod108 ACC>AAC or α1[α108(G15)Thr→Asn] and the Hb Policoro, α2 cod124 TCC>CCC or α2[α124(H7)Ser→Pro]. The carriers showed mild α-thalassemia phenotype and abnormal hemoglobin stability features. These mutations occurred in the G and H helices of the α-globin both involved in the specific recognition of AHSP and β1 chain. Molecular characterization of mRNA, globin chain analyses and molecular modelling studies were carried out to highlight the mechanisms causing the α-thalassemia phenotype. The results demonstrated that the α-thalassemia defect associated with the two Hb variants originated by different defects. Hb Rogliano showed an intrinsic instability of the tetramer due to anomalous intra- and inter-chain interactions suggesting that the variant chain is normally synthesized and complexed with AHSP but rapidly degraded because it is unable to form the α1β1 dimers. On the contrary in the case of Hb Policoro two different molecular mechanisms were shown: the reduction of the variant mRNA level by an unclear mechanism and the protein instability due to impairment of AHSP interaction. These data highlighted that multiple approaches, including mRNA quantification, are needed to properly identify the mechanisms leading to the α-thalassemia defect. Elucidation of the specific mechanism leads to the definition of a given phenotype providing important guidance for the diagnosis of unstable variants.

ACS Style

Maria Grazia Bisconte; Mercedes Caldora; Gennaro Musollino; Giovanna Cardiero; Angela Flagiello; Gaetana La Porta; Laura Lagona; Romeo Prezioso; Gabriele Qualtieri; Carlo Gaudiano; Emilia Medulla; Antonello Merlino; Pietro Pucci; Giuseppina Lacerra. α-Thalassemia Associated with Hb Instability: A Tale of Two Features. The Case of Hb Rogliano or α1 Cod 108(G15)Thr→Asn and Hb Policoro or α2 Cod 124(H7)Ser→Pro. PLOS ONE 2015, 10, e0115738 .

AMA Style

Maria Grazia Bisconte, Mercedes Caldora, Gennaro Musollino, Giovanna Cardiero, Angela Flagiello, Gaetana La Porta, Laura Lagona, Romeo Prezioso, Gabriele Qualtieri, Carlo Gaudiano, Emilia Medulla, Antonello Merlino, Pietro Pucci, Giuseppina Lacerra. α-Thalassemia Associated with Hb Instability: A Tale of Two Features. The Case of Hb Rogliano or α1 Cod 108(G15)Thr→Asn and Hb Policoro or α2 Cod 124(H7)Ser→Pro. PLOS ONE. 2015; 10 (3):e0115738.

Chicago/Turabian Style

Maria Grazia Bisconte; Mercedes Caldora; Gennaro Musollino; Giovanna Cardiero; Angela Flagiello; Gaetana La Porta; Laura Lagona; Romeo Prezioso; Gabriele Qualtieri; Carlo Gaudiano; Emilia Medulla; Antonello Merlino; Pietro Pucci; Giuseppina Lacerra. 2015. "α-Thalassemia Associated with Hb Instability: A Tale of Two Features. The Case of Hb Rogliano or α1 Cod 108(G15)Thr→Asn and Hb Policoro or α2 Cod 124(H7)Ser→Pro." PLOS ONE 10, no. 3: e0115738.

Journal article
Published: 28 June 2013 in Haematologica
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ACS Style

Maria De Angioletti; Vincenzo Sabato; Gennaro Musollino; Romeo Prezioso; Clementina Carestia; Giuseppina Lacerra. South-Italy -thalassemia: a novel deletion not removing the -globin silencing element and with 3' breakpoint in a hsRTVL-H element, associated with -thalassemia and high levels of HbF. Haematologica 2013, 98, e98 -e100.

AMA Style

Maria De Angioletti, Vincenzo Sabato, Gennaro Musollino, Romeo Prezioso, Clementina Carestia, Giuseppina Lacerra. South-Italy -thalassemia: a novel deletion not removing the -globin silencing element and with 3' breakpoint in a hsRTVL-H element, associated with -thalassemia and high levels of HbF. Haematologica. 2013; 98 (8):e98-e100.

Chicago/Turabian Style

Maria De Angioletti; Vincenzo Sabato; Gennaro Musollino; Romeo Prezioso; Clementina Carestia; Giuseppina Lacerra. 2013. "South-Italy -thalassemia: a novel deletion not removing the -globin silencing element and with 3' breakpoint in a hsRTVL-H element, associated with -thalassemia and high levels of HbF." Haematologica 98, no. 8: e98-e100.