Jean Delaunay

Publications (66)325.68 Total impact

• Article: Unusual low sickle cell hemoglobin level.

  Faouzi Baklouti, Jean Delaunay
  Haematologica 06/2013; 98(6):e64. · 6.42 Impact Factor
• Source

  Available from: Annalisa Vetro

  Article: Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1.

  Immacolata Andolfo, Seth L Alper, Lucia De Franceschi, Carla Auriemma, Roberta Russo, Luigia De Falco, Fara Vallefuoco, Maria Rosaria Esposito, David H Vandorpe, Boris E Shmukler, [......], Maria D'Armiento, Annalisa Vetro, Ivan Limongelli, Orsetta Zuffardi, Bertil E Glader, Stanley L Schrier, Carlo Brugnara, Gordon W Stewart, Jean Delaunay, Achille Iolascon
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  ABSTRACT: Key points Dehydrated hereditary stomatocytosis is characterized by abnormal RBC morphology but may also involve pseudohyperkalemia and perinatal edema.This syndrome is associated with germline mutations in PIEZO1, encoding a transmembrane protein that induces mechanosensitive currents.
  Blood 03/2013; · 9.90 Impact Factor
• Source

  Available from: Immacolata Andolfo

  Article: Missense mutations in the ABCB6 transporter cause dominant familialpseudohyperkalemia.

  Immacolata Andolfo, Seth L Alper, Jean Delaunay, Carla Auriemma, Roberta Russo, Roberta Asci, Maria Rosaria Esposito, Alok K Sharma, Boris E Shmukler, Carlo Brugnara, Lucia De Franceschi, Achille Iolascon
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  ABSTRACT: Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by increased serum [K(+) ] in whole blood stored at or below room temperature, without additional hematological abnormalities. Functional gene mapping and sequencing analysis of the candidate genes within the 2q35-q36 critical interval identified-in 20 affected individuals among three multigenerational FP families-two novel heterozygous missense mutations in the ABCB6 gene that cosegregated with disease phenotype. The two genomic substitutions altered two adjacent nucleotides within codon 375 of ABCB6, a porphyrin transporter that, in erythrocyte membranes, bears the Langereis blood group antigen system. The ABCB6 R375Q mutation did not alter the levels of mRNA or protein, or protein localization in mature erythrocytes or erythroid precursor cells, but it is predicted to modestly alter protein structure. ABCB6 mRNA and protein levels increase during in vitro erythroid differentiation of CD34(+) erythroid precursors and the erythroleukemia cell lines HEL and K562. These data suggest that the two missense mutations in residue 375 of the ABCB6 polypeptide found in affected individuals of families with chromosome 2-linked FP could contribute to the red cell K(+) leak characteristic of this condition. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.
  American Journal of Hematology 10/2012; · 4.67 Impact Factor
• Article: Kaposi’s sarcoma in a child with Wiskott-Aldrich syndrome

  Capucine Picard, Fethi Mellouli, Renan Duprez, Gaëlle Chédeville, Bénédicte Neven, Sylvie Fraitag, Jean Delaunay, Françoise Le Deist, Alain Fischer, Stéphane Blanche, Christine Bodemer, Antoine Gessain, Jean-Laurent Casanova, Mohamed Bejaoui
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  ABSTRACT: IntroductionKaposi’s sarcoma (KS) is rare in childhood. It may be favored by acquired immune deficiencies, but the predisposing factors to KS in other children are unclear.DiscussionKS has been reported in only two children and one adult with primary immunodeficiency. We report here a Tunisian child with a Wiskott-Aldrich syndrome who developed KS at the age of 14months.ConclusionThis observation expands the spectrum of primary immunodeficiencies associated with KS in childhood.
  European Journal of Pediatrics 04/2012; 165(7):453-457. · 1.88 Impact Factor
• Article: Human RhAG ammonia channel is impaired by the Phe65Ser mutation in overhydrated stomatocytic red cells.

  Sandrine Genetet, Pierre Ripoche, Julien Picot, Sylvain Bigot, Jean Delaunay, Corinne Armari-Alla, Yves Colin, Isabelle Mouro-Chanteloup
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  ABSTRACT: In red cells, Rh-associated glycoprotein (RhAG) acts as an ammonia channel, as demonstrated by stopped-flow analysis of ghost intracellular pH (pH(i)) changes. Recently, overhydrated hereditary stomatocytosis (OHSt), a rare dominantly inherited hemolytic anemia, was found to be associated with a mutation (Phe65Ser or Ile61Arg) in RHAG. Ghosts from the erythrocytes of four of the OHSt patients with a Phe65Ser mutation were resealed with a pH-sensitive probe and submitted to ammonium gradients. Alkalinization rate constants, reflecting NH(3) transport through the channel and NH(3) diffusion unmediated by RhAG, were deduced from time courses of fluorescence changes. After subtraction of the constant value found for Rh(null) lacking RhAG, we observed that alkalinization rate constant values decreased ∼50% in OHSt compared with those of controls. Similar RhAG expression levels were found in control and OHSt. Since half of the expressed RhAG in OHSt most probably corresponds to the mutated form of RhAG, as expected from the OHSt heterozygous status, this dramatic decrease can be therefore related to the loss of function of the Phe65Ser-mutated RhAG monomer.
  AJP Cell Physiology 01/2012; 302(2):C419-28. · 3.54 Impact Factor
• Source

  Available from: Roberta Russo

  Article: Two founder mutations in the SEC23B gene account for the relatively high frequency of CDA II in the Italian population.

  Roberta Russo, Antonella Gambale, Maria Rosaria Esposito, Maria Luisa Serra, Annaelena Troiano, Ilaria De Maggio, Mario Capasso, Lucio Luzzatto, Jean Delaunay, Hannah Tamary, Achille Iolascon
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  ABSTRACT: Congenital Dyserythropoietic Anemia type II is an autosomal recessive disorder characterized by unique abnormalities in the differentiation of cells of the erythroid lineage. The vast majority of CDA II cases result from mutations in the SEC23B gene. To date, 53 different causative mutations have been reported in 86 unrelated cases (from the CDA II European Registry), 47 of them Italian. We have now identified SEC23B mutations in 23 additional patients, 17 Italians and 6 non-Italian Europeans. The relative allelic frequency of the mutations was then reassessed in a total of 64 Italian and 45 non-Italian unrelated patients. Two mutations, E109K and R14W, account for over one-half of the cases of CDA II in Italy. Whereas the relative frequency of E109K is similar in Italy and in the rest of Europe (and is also prevalent in Moroccan Jews), the relative frequency of R14W is significantly higher in Italy (26.3% vs. 10.7%). By haplotype analysis we demonstrated that both are founder mutations in the Italian population. By using the DMLE+ program our estimate for the age of the E109K mutation in Italian population is ≈2,200 years; whereas for the R14W mutation it is ≈3,000 years. We hypothesize that E109K may have originated in the Middle East and may have spread in the heyday of the Roman Empire. Instead, R14W may have originated in Southern Italy. The relatively high frequency of the R14W mutation may account for the known increased prevalence of CDA II in Italy.
  American Journal of Hematology 09/2011; 86(9):727-32. · 4.67 Impact Factor
• Article: Homozygous deletion of EPB41 genuine AUG-containing exons results in mRNA splicing defects, NMD activation and protein 4.1R complete deficiency in hereditary elliptocytosis.

  Faouzi Baklouti, Madeleine Morinière, Amel Haj-Khélil, Madeleine Fénéant-Thibault, Henri Gruffat, Yohann Couté, Alain Ninot, Corinne Guitton, Jean Delaunay
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  ABSTRACT: Complete loss of protein 4.1R in red blood cell membrane is a very rare condition in humans. We here explore the third case. The morphological and biochemical observations suggested that the proband suffers from homozygous hereditary elliptocytosis. Both parents, who are consanguineous, have an elliptocytosis with no cell fragmentation, typical of a heterozygous 4.1R deficiency with a silent allele. A genomic deletion was found; it encompasses about 50 kb of genomic DNA, and suppresses the two key exons 2 and 4, which contain the two functional AUG translation initiation sites in erythroid and nonerythroid cells. The alternative first exons are intact, hence preserving the transcription potential of the altered gene. Extensive analysis of 4.1R transcripts revealed multiple splicing defects upstream of the deleted sequences. Importantly, we found that most of the transcripts generated from the altered gene are intercepted by the nonsense-mediated mRNA decay mechanism, suggesting that the massive degradation of the mRNA species jeopardizes the production of shortened but functional protein 4.1R from an alternative translation initiation site downstream of the deletion.
  Blood Cells Molecules and Diseases 08/2011; 47(3):158-65. · 2.35 Impact Factor
• Source

  Available from: Philippe Quittet

  Article: Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome.

  Joanna F Flatt, Hélène Guizouarn, Nicholas M Burton, Franck Borgese, Richard J Tomlinson, Robert J Forsyth, Stephen A Baldwin, Bari E Levinson, Philippe Quittet, Patricia Aguilar-Martinez, Jean Delaunay, Gordon W Stewart, Lesley J Bruce
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  ABSTRACT: The hereditary stomatocytoses are a series of dominantly inherited hemolytic anemias in which the permeability of the erythrocyte membrane to monovalent cations is pathologically increased. The causative mutations for some forms of hereditary stomatocytosis have been found in the transporter protein genes, RHAG and SLC4A1. Glucose transporter 1 (glut1) deficiency syndromes (glut1DSs) result from mutations in SLC2A1, encoding glut1. Glut1 is the main glucose transporter in the mammalian blood-brain barrier, and glut1DSs are manifested by an array of neurologic symptoms. We have previously reported 2 cases of stomatin-deficient cryohydrocytosis (sdCHC), a rare form of stomatocytosis associated with a cold-induced cation leak, hemolytic anemia, and hepatosplenomegaly but also with cataracts, seizures, mental retardation, and movement disorder. We now show that sdCHC is associated with mutations in SLC2A1 that cause both loss of glucose transport and a cation leak, as shown by expression studies in Xenopus oocytes. On the basis of a 3-dimensional model of glut1, we propose potential mechanisms underlying the phenotypes of the 2 mutations found. We investigated the loss of stomatin during erythropoiesis and find this occurs during reticulocyte maturation and involves endocytosis. The molecular basis of the glut1DS, paroxysmal exercise-induced dyskinesia, and sdCHC phenotypes are compared and discussed.
  Blood 07/2011; 118(19):5267-77. · 9.90 Impact Factor
• Article: Wiskott-Aldrich syndrome presenting with early onset recurrent acute hemorrhagic edema and hyperostosis.

  Shanmuganathan Chandrakasan, Surjit Singh, Sunil Dogra, Jean Delaunay, Alexis Proust, Ranjana W Minz
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  ABSTRACT: We report two unusual presenting manifestations of Wiskott-Aldrich syndrome (WAS), recurrent acute hemorrhagic edema of infancy (AHEI); a form of cutaneous vasculitis and hyperostosis of the tibia. Though cutaneous vasculitis is known to occur in WAS, presentation in early infancy and as AHEI is extremely uncommon. Hyperostosis is not a well-recognized association in WAS; only three patients with this association have been previously reported. In our patient these two unusual manifestations preceded the onset of recurrent infections. Recognition of this rare presentation led us to an early diagnosis of WAS, associated with p.Glu31Lys mutation in the WAS protein.
  Pediatric Blood & Cancer 07/2011; 56(7):1130-2. · 1.89 Impact Factor
• Article: Congenital dyserythropoietic anemias.

  Achille Iolascon, Roberta Russo, Jean Delaunay
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  ABSTRACT: Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders characterized by ineffective erythropoiesis and by distinct morphological abnormalities of erythroblasts in the bone marrow. Characteristic morphological aberrations were the cornerstone of diagnosis, but following the identification of several causative genes, the molecular approach could represent a rapid tool for the identification of these conditions. This review presents advances in diagnosis and classification of CDAs. The classification of CDAs has long been based on morphological features. Now, the discovery of some of the responsible genes allows reconsideration of part of the classification. The first CDA partly accounted for genetically has been CDA 1, through the discovery in 2002 of the gene responsible, CDAN1, encoding codanin-1. Recently, the dramatic identification of the genes responsible for CDA II, SEC23B, and for a hitherto unnamed CDA, KLF1, took place. SEC23B encodes SEC23B which is a component of the coated vesicles transiting from the endoplasmic reticulum to the cis compartment of the Golgi apparatus. A unique mutation in KLF1, which encodes the erythroid transcription factor KLF1, causes major ultrastructural abnormalities, the persistence of embryonic and fetal hemoglobins, and the absence of some red cell membrane proteins. Studies of genotype-phenotype relationship, as has already been done for CDA II, will allow a more accurate prognosis. Identification of the responsible genes has opened new vistas for research on CDAs.
  Current opinion in hematology 03/2011; 18(3):146-51. · 5.19 Impact Factor
• Article: F65S Mutation in RhAG is Associated with Decreased Ammonia Flux Through Overhydrated Stomatocytic Erythrocytes

  Sandrine Genetet, Pierre Ripoche, Julien Picot, Sylvain Bigot, Jean Delaunay, Corinne Amari-Alla, Yves Colin, Isabelle Mouro-Chanteloup
  Biophysical Journal - BIOPHYS J. 01/2011; 100(3).
• Article: Nonsense-mediated mRNA decay (NMD) blockage promotes nonsense mRNA stabilization in protein 4.1R deficient cells carrying the 4.1R Coimbra variant of hereditary elliptocytosis.

  Madeleine Morinière, François Delhommeau, Alain Calender, Leticia Ribeiro, Jean Delaunay, Faouzi Baklouti
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  ABSTRACT: We describe a new approach to stabilize nonsense mRNA, based on the inhibition of the NMD mechanism, by combining cycloheximide-mediated inhibition of translation, and caffeine-mediated inhibition of UPF1 phosphorylation. This approach aimed to identify the impact of a 4.1R splicing mutation. This mutation is involved in a partial deficiency of 4.1R in the homozygous state in a patient with hereditary elliptocytosis and a moderated hemolytic anemia. We show that, in addition to two known minor shortened and stable spliceoforms, the mutation activates an intronic cryptic splice site, which results in a nonsense mRNA major isoform, targeted to degradation in intact cells by NMD. This accounts for the main cause of 4.1R partial deficiency. In a general perspective, blocking the NMD mechanism would help to identify a missing isoform, and pave the path for a molecular targeting strategy to circumvent a deleterious splicing pathway in favor of a therapeutic splicing pathway.
  Blood Cells Molecules and Diseases 12/2010; 45(4):284-8. · 2.35 Impact Factor
• Source

  Available from: Thierry Peyrard

  Article: A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia.

  Lionel Arnaud, Carole Saison, Virginie Helias, Nicole Lucien, Dominique Steschenko, Marie-Catherine Giarratana, Claude Prehu, Bernard Foliguet, Lory Montout, Alexandre G de Brevern, [......], Lydie Da Costa, Thierry Peyrard, Gail Coghlan, Niels Illum, Henrik Birgens, Hannah Tamary, Achille Iolascon, Jean Delaunay, Gil Tchernia, Jean-Pierre Cartron
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  ABSTRACT: The congenital dyserythropoietic anemias (CDAs) are inherited red blood cell disorders whose hallmarks are ineffective erythropoiesis, hemolysis, and morphological abnormalities of erythroblasts in bone marrow. We have identified a missense mutation in KLF1 of patients with a hitherto unclassified CDA. KLF1 is an erythroid transcription factor, and extensive studies in mouse models have shown that it plays a critical role in the expression of globin genes, but also in the expression of a wide spectrum of genes potentially essential for erythropoiesis. The unique features of this CDA confirm the key role of KLF1 during human erythroid differentiation. Furthermore, we show that the mutation has a dominant-negative effect on KLF1 transcriptional activity and unexpectedly abolishes the expression of the water channel AQP1 and the adhesion molecule CD44. Thus, the study of this disease-causing mutation in KLF1 provides further insights into the roles of this transcription factor during erythropoiesis in humans.
  The American Journal of Human Genetics 11/2010; 87(5):721-7. · 10.60 Impact Factor
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  Available from: Roberta Russo

  Article: Mutational spectrum in congenital dyserythropoietic anemia type II: identification of 19 novel variants in SEC23B gene.

  Roberta Russo, Maria Rosaria Esposito, Roberta Asci, Antonella Gambale, Silverio Perrotta, Ugo Ramenghi, Gian Luca Forni, Vedat Uygun, Jean Delaunay, Achille Iolascon
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  ABSTRACT: SEC23B gene encodes an essential component of the coat protein complex II (COPII)-coated vesicles. Mutations in this gene cause the vast majority the congenital dyserythropoietic anemia Type II (CDA II), a rare disorder resulting from impaired erythropoiesis. Here, we investigated 28 CDA II patients from 21 unrelated families enrolled in the CDA II International Registry. Overall, we found 19 novel variants [c.2270 A>C p.H757P; c.2149-2 A>G; c.1109+1 G>A; c.387(delG) p.L129LfsX26; c.1858 A>G p.M620V; c.1832 G>C p.R611P; c.1735 T>A p.Y579N; c.1254 T>G p.I418M; c.1015 C>T p.R339X; c.1603 C>T p.R535X; c.1654 C>T p.L552F; c.1307 C>T p.S436L; c.279+3 A>G; c. 2150(delC) p.A717VfsX7; c.1733 T>C p.L578P; c.1109+5 G>A; c.221+31 A>G; c.367 C>T p.R123X; c.1857_1859delCAT; p.I619del] in the homozygous or the compound heterozygous state. Homozygosity or compound heterozygosity for two nonsense mutations was never found. In four cases the sequencing analysis has failed to find two mutations. To discuss the putative functional consequences of missense mutations, computational analysis and sequence alignment were performed. Our data underscore the high allelic heterogeneity of CDA II, as the most of SEC23B variations are inherited as private mutations. In this mutation update, we also provided a tool to improve and facilitate the molecular diagnosis of CDA II by defining the frequency of mutations in each exon.
  American Journal of Hematology 09/2010; 85(12):915-20. · 4.67 Impact Factor
• Article: Frequency of congenital dyserythropoietic anemias in Europe.

  Hermann Heimpel, Andreas Matuschek, Momin Ahmed, Brigitte Bader-Meunier, Adriana Colita, Jean Delaunay, Loic Garcon, Florinda Gilsanz, Jeroen Goede, Josef Högel, [......], Rosi Leichtle, Juan Munoz, Silverio Perrotta, Carlo Piscopo, Raffaele Renella, Klaus Schwarz, Gabriela Smolenska-Sym, Sunitha Wickramasinghe, Alberto Zanella, Achille Iolascon
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  ABSTRACT: Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders characterized by ineffective erythropoiesis and striking abnormalities of erythroblast morphology. The mutated genes are known for the most frequent types, CDA I and II, but data about their frequency do not exist. The objective of this retrospective study was to estimate the frequency of CDA I and II, based on all cases reported in the last 42 yr in publications and identified registries or surveys. Reports were collected of 124 and 377 confirmed cases of CDA I and CDA II cases, respectively. The cumulated incidence of both types combined varied widely between European regions, with minimal values of 0.08 cases/million in Scandinavia and 2.60 cases/million in Italy. CDA II is more frequent than CDA I, with an overall ratio of approximately 3.2, but the ratio also varied between different regions. The most likely explanations for the differences are both differences in the availability of advanced diagnostic procedures and different levels of the awareness for the diagnosis of the CDAs. The estimations reported here are most probably below the true incidence rates, because of failure to make the correct diagnosis and to underreporting. Limited data do not suggest differing levels of risk in identified ethnic groups.
  European Journal Of Haematology 07/2010; 85(1):20-5. · 2.61 Impact Factor
• Article: Genetic variants in the noncoding region of RPS19 gene in Diamond-Blackfan anemia: potential implications for phenotypic heterogeneity.

  Aurore Crétien, Alexis Proust, Jean Delaunay, Patricia Rincé, Thierry Leblanc, Rolande Ducrocq, Maud Simansour, Isabelle Marie, Hannah Tamary, Jörg Meerpohl, Charlotte Niemeyer, Hanna Gazda, Colin Sieff, Sarah Ball, Gil Tchernia, Narla Mohandas, Lydie Da Costa
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  ABSTRACT: Mutations in the RPS19 gene have been identified in 25% of individuals affected by Diamond-Blackfan anemia (DBA), a congenital erythroblastopenia characterized by an aregenerative anemia and a variety of malformations. More than 60 mutations in the five coding exons of RPS19 have been described to date. We previously reported a mutation (c.-1 + 26G>T) and an insertion at -631 upstream of ATG (c.-147_-146insGCCA) in the noncoding region. Because DBA phenotype is extremely heterogeneous from silent to severe and because haploinsufficiency seems to play a role in this process, it is likely that genetic variations in the noncoding regions affecting translation of RPS19 can modulate the phenotypic expression of DBA. However, to date, very few studies have addressed this question comprehensively. In this study, we performed detailed sequence analysis of the RPS19 gene in 239 patients with DBA and 110 of their relatives. We found that 6.2% of the patients with DBA carried allelic variations upstream of ATG: 3.3% with c.-1 + 26G>T; 2.5% with c.-147_-146insGCCA; and 0.4% with c.-174G>A. Interestingly, the c.-147_-146insGCCA, which has been found in a black American and French Caribbean control population, was not found in 500 Caucasian control chromosomes we studied. However, it was found in association with the same haplotype distribution of four intronic polymorphisms in our patients with DBA. Although a polymorphism, the frequency of this variant in the patients with DBA and its association with the same haplotype raises the possibility that this polymorphism and the other genetic variations in the noncoding region could play a role in DBA pathogenesis.
  American Journal of Hematology 02/2010; 85(2):111-6. · 4.67 Impact Factor
• Article: Role of the interaction between Lu/BCAM and the spectrin-based membrane skeleton in the increased adhesion of hereditary spherocytosis red cells to laminin.

  Emilie Gauthier, Wassim El Nemer, Marie P Wautier, Olivier Renaud, Gil Tchernia, Jean Delaunay, Caroline Le Van Kim, Yves Colin
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  ABSTRACT: Lu/BCAM, the unique erythroid receptor for laminin 511/521, interacts with the erythrocyte membrane skeleton through spectrin binding. It has been reported that Hereditary Spherocytosis red blood cells (HS RBC) exhibit increased adhesion to laminin. We investigated the role of Lu/BCAM-spectrin interaction in the RBC adhesion properties of 2 splenectomised HS patients characterized by 40% spectrin deficiency. Under physiological flow conditions, HS RBC exhibited an exaggerated adhesion to laminin that was completely abolished by soluble Lu/BCAM. Triton extraction experiments revealed that a greater fraction of Lu/BCAM was unlinked to the membrane skeleton of HS RBC, as compared to normal RBC. Disruption of the spectrin interaction site in Lu/BCAM expressed in the transfected K562 cell line resulted in a weakened interaction to the skeleton and an enhanced interaction to laminin. These results demonstrated that the adhesion of HS RBC to laminin was mediated by Lu/BCAM and that its interaction with the spectrin-based skeleton negatively regulated cell adhesion to laminin. Finally, the results of this study strongly suggest that the reinforced adhesiveness of spectrin-deficient HS RBC to laminin is partly brought about by an impaired interaction between Lu/BCAM and the membrane skeleton.
  British Journal of Haematology 02/2010; 148(3):456-65. · 4.94 Impact Factor
• Article: Investigating the key membrane protein changes during in vitro erythropoiesis of protein 4.2 (-) cells (mutations Chartres 1 and 2).

  Emile van den Akker, Timothy J Satchwell, Stephanie Pellegrin, Joanna F Flatt, Michel Maigre, Geoff Daniels, Jean Delaunay, Lesley J Bruce, Ashley M Toye
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  ABSTRACT: Protein 4.2 deficiency caused by mutations in the EPB42 gene results in hereditary spherocytosis with characteristic alterations of CD47, CD44 and RhAG. We decided to investigate at which stage of erythropoiesis these hallmarks of protein 4.2 deficiency arise in a novel protein 4.2 patient and whether they cause disruption to the band 3 macrocomplex. We used immunoprecipitations and detergent extractability to assess the strength of protein associations within the band 3 macrocomplex and with the cytoskeleton in erythrocytes. Patient erythroblasts were cultured from peripheral blood mononuclear cells to study the effects of protein 4.2 deficiency during erythropoiesis. We report a patient with two novel mutations in EPB42 resulting in complete protein 4.2 deficiency. Immunoprecipitations revealed a weakened ankyrin-1-band 3 interaction in erythrocytes resulting in increased band 3 detergent extractability. CD44 abundance and its association with the cytoskeleton were increased. Erythroblast differentiation revealed that protein 4.2 and band 3 appear simultaneously and associate early in differentiation. Protein 4.2 deficiency results in lower CD47, higher CD44 expression and increased RhAG glycosylation starting from the basophilic stage. The normal downregulation of CD44 expression was not seen during protein 4.2(-) erythroblast differentiation. Knockdown of CD47 did not increase CD44 expression, arguing against a direct reciprocal relationship. We have established that the characteristic changes caused by protein 4.2 deficiency occur early during erythropoiesis. We postulate that weakening of the ankyrin-1-band 3 association during protein 4.2 deficiency is compensated, in part, by increased CD44-cytoskeleton binding.
  Haematologica 02/2010; 95(8):1278-86. · 6.42 Impact Factor
• Article: A dyserythropoietic anemia associated with homozygous Hb Plasencia [α125(H8)Leu→Arg (α2)] (HBA2:c.377T>G), a variant with an unstable α chain.

  Loïc Garçon, Achille Iolascon, Serge Pissard, Maria R Esposito, Roberta Russo, Odile Fenneteau, Madeleine Fénéant-Thibault, Hermann Heimpel, Jean Delaunay
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  ABSTRACT: A female patient of Portuguese origin, who was born to consanguineous parents, presented with moderate anemia, mild jaundice and splenomegaly. Bone marrow aspiration showed an erythroid hyperplasia and binucleate erythroblasts, evoking a congenital dyserythropoietic anemia, type II (CDA II). Although microcytosis cast some doubt on the diagnosis, investigation was pursued along this line. The CDA II was finally ruled out as underglycosylation of band 3, remnants of endoplasmic reticulum cisternae and mutations in the SEC23B gene were all missing. On the other hand, analysis of the α-globin genes showed a base substitution at codon 125 (CTG→CGG) of the α2-globin gene, ascertaining a homozygosity for Hb Plasencia (HBA2:c.377T>G). This variant has an unstable α chain. In the absence of a thorough work-up, dyserythropoietic anemia associated with hemoglobin (Hb) variants having a moderately unstable α chain, may be mistaken for CDA II.
  Hemoglobin 01/2010; 34(6):576-81. · 1.30 Impact Factor
• Source

  Available from: Roberta Russo

  Article: Molecular analysis of 42 patients with congenital dyserythropoietic anemia type II: new mutations in the SEC23B gene and a search for a genotype-phenotype relationship.

  Achille Iolascon, Roberta Russo, Maria Rosaria Esposito, Roberta Asci, Carmelo Piscopo, Silverio Perrotta, Madeleine Fénéant-Thibault, Loïc Garçon, Jean Delaunay
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  ABSTRACT: The most frequent form of congenital dyserythropoietic anemia is the type II form. Recently it was shown that the vast majority of patients with congenital dyserythropoietic anemia type II carry mutations in the SEC23B gene. Here we established the molecular basis of 42 cases of congenital dyserythropoietic anemia type II and attempted to define a genotype-phenotype relationship. SEC23B gene sequencing analysis was performed to assess the diversity and incidence of each mutation in 42 patients with congenital dyserythropoietic anemia type II (25 described exclusively in this work), from the Italian and the French Registries, and the relationship of these mutations with the clinical presentation. To this purpose, we divided the patients into two groups: (i) patients with two missense mutations and (ii) patients with one nonsense and one missense mutation. We found 22 mutations of uneven frequency, including seven novel mutations. Compound heterozygosity for a missense and a nonsense mutation tended to produce a more severe clinical presentation, a lower reticulocyte count, a higher serum ferritin level, and, in some cases, more pronounced transfusion needs, than homozygosity or compound heterozygosity for two missense mutations. Homozygosity or compound heterozygosity for two nonsense mutations was never found. This study allowed us to determine the most frequent mutations in patients with congenital dyserythropoietic anemia type II. Correlations between the mutations and various biological parameters suggested that the association of one missense mutation and one nonsense mutation was significantly more deleterious that the association of two missense mutations. However, there was an overlap between the two categories.
  Haematologica 12/2009; 95(5):708-15. · 6.42 Impact Factor