Hereditary hemoglobin disorders: molecular genetics, clinical features and animal models with the production of transgenic animals

• Grant number: 02/13801-7
• Support Opportunities: Research Projects - Thematic Grants
• Start date: November 01, 2003
• End date: December 31, 2008
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fernando Ferreira Costa
• Grantee: Fernando Ferreira Costa
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Pesquisadores principais: Maria de Fatima Sonati
• Associated scholarship(s): 07/08585-7 - Effect of simvastatin and sildenafil on the inflammatory process in sickle cell disease: A rondomized pilot, simple-blind and placebo control study in animal model and patients, BP.PD

Abstract

We intend to study gene expression in hereditary persistence of fetal hemoglobin, beta thalassemia (with the same genotype but with different phenotypes) and hemoglobin H disease using differential display and serial analysis of gene expression (SAGE), taking advantage of the high throughput sequencing machines that we have in our laboratory. The differentially expressed genes will be studied with respect to their function in hemopoiesis. In addition, two genes with possibly significant roles in hemoglobin disorders will be analyzed: the recently described alpha hemoglobin stabilizing protein gene and a human analogue of the SARA gene type with a possible function for protein transport across membranes. We propose to produce a transgenic mouse with the gamma gene responsible for the Brazilian type of HPFH and other animals with specific rearrangements of the beta globin cluster, aiming to study mechanisms of fetal hemoglobin production. A number of clinical and laboratory studies will be carried out with the objective of analyzing possible associations between molecular and clinical features. To this end, we will perform a comprehensive analysis of coagulation and thrombosis abnormalities in patients with hemoglobinopathies. Several molecular aspects of rare red blood cell antigens will also be investigated. Moreover, adhesion properties of neutrophils and eosinophils will be studied in these disorders, since these cells apparently play a critical role in the vasooclusive phenomenon of sickle cell disease. Stroke is a major cause of morbidity and mortality in sickle cell disease. Genetic risk factors have been postulated to contribute to this clinical outcome. We propose, herein, a genome wide scan to find genes that may modify the risk for manifestation of disease outcome. The routine search for molecular abnormalities of beta and alpha globin genes in patients with beta and alpha thalassemia or with structural variants will be continued, since this kind of information may result in important data to increase the knowledge of the gene and protein function. Currently, our hemoglobin laboratory in Campinas receives samples from all states of Brazil and other South American countries. (AU)

Scientific publications

(22)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DOS SANTOS, CAMILA O.; DORE, LOUIS C.; VALENTINE, ERIC; SHELAT, SURESH G.; HARDISON, ROSS C.; GHOSH, MANIK; WANG, WEI; EISENSTEIN, RICHARD S.; COSTA, FERNANDO F.; WEISS, MITCHELL J.. An iron responsive element-like stem-loop regulates alpha-hemoglobin-stabilizing protein mRNA. Journal of Biological Chemistry, v. 283, n. 40, p. 26956-26964, OCT 3 2008. (02/13801-7)

RIBEIRO, D. M.; SONATI, M. F.. Regulation of human alpha-globin gene expression and alpha-thalassemia. Genetics and Molecular Research, v. 7, n. 4, p. 1045-1053, 2008. (02/13801-7)

DA CUNHA, A. F.; BRUGNEROTTO, A. F.; DUARTE, A. S.; LANARO, C.; COSTA, G. G. L.; SAAD, S. T. O.; COSTA, F. F.. Global gene expression reveals a set of new genes involved in the modification of cells during erythroid differentiation. Cell Proliferation, v. 43, n. 3, p. 297-309, JUN 2010. (02/13801-7)

D.M. RIBEIRO; T.R. ZACCARIOTTO; M.N.N. SANTOS; F.F. COSTA; M.F. SONATI. Influence of the polymorphisms of the α-major regulatory element HS-40 on in vitro gene expression. Brazilian Journal of Medical and Biological Research, v. 42, n. 9, p. 783-786, 2009-07-31. (02/13801-7)

MARIA DE FÁTIMA SONATI; FERNANDO FERREIRA COSTA. Genética das doenças hematológicas: as hemoglobinopatias hereditárias. Jornal de Pediatria, v. 84, n. 4, p. S40-S51, 2008-08-00. (02/13801-7)

HOLLANDA, LUCIANA M.; LIMA, CARMEN S. P.; CUNHA, ANDERSON F.; ALBUQUERQUE, DULCINÉIA M.; VASSALLO, JOSÉ; OZELO, MARGARETH C.; JOAZEIRO, PAULO P.; SAAD, SARA T. O.; COSTA, FERNANDO F.. An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis. Nature Genetics, v. 38, n. 7, p. 807-812, July 2006. (02/13801-7)

PINHO, FLAVIA OLIVEIRA; ALBUQUERQUE, DULCINEIA MARTINS DE; SAAD, SARA TERESINHA OLALLA; COSTA, FERNANDO FERREIRA. Reduction of AHSP synthesis in hemin-induced K562 cells and EPO-induced CD34(+) cells leads to alpha-globin precipitation, impairment of normal hemoglobin production, and increased cell death. Experimental Hematology, v. 36, n. 3, p. 265-272, Mar. 2008. (02/13801-7)

WEINSTEIN, B. I.; ERRAMOUSPE, B.; ALBUQUERQUE, D. M.; OLIVEIRA, D. M.; KIMURA, E. M.; COSTA, F. F.; SONATI, M. F.. Hb Florida: a novel elongated C-terminal beta-globin variant causing dominant beta-thalassemia phenotype. American Journal of Hematology, v. 81, n. 5, p. 358-360, May 2006. (02/13801-7)

COSTA, FLÁVIA CHAGAS; CUNHA, ANDERSON FERREIRA DA; FATTORI, ANDRÉ; PERES, TARCÍSIO DE SOUSA; COSTA, GUSTAVO GILSON LACERDA; MACHADO, TIAGO FERRAZ; ALBUQUERQUE, DULCINÉIA MARTINS DE; GAMBERO, SHELEY; LANARO, CAROLINA; SAAD, SARA T. OLALA; et al. Gene expression profiles of erythroid precursors characterise several mechanisms of the action of hydroxycarbamide in sickle cell anaemia. British Journal of Haematology, v. 136, n. 2, Jan. 2007. (02/13801-7)

ROVERSI, FERNANDA MARCONI; DA CUNHA, ANDERSON FERREIRA; BRUGNEROTTO, ANA FLAVIA; CARAZZOLLE, MARCELO FALSARELLA; DE ALBUQUERQUE, DULCINEIA MARTINS; LANARO, CAROLINA; MACHADO-NETO, JOAO AGOSTINHO; OLALLA SAAD, SARA TERESINHA; DA COSTA, FERNANDO FERREIRA. GENE EXPRESSION ANALYSIS OF THE BRAZILIAN TYPE OF HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN: IDENTIFICATION OF GENES THAT COULD BE RELATED TO gamma-GLOBIN ACTIVATION. HEMOGLOBIN, v. 37, n. 6, p. 516-535, 2013. (02/13801-7)

BEZERRA, MARCOS A. C.; ALBUQUERQUE, DULCINEIA M.; SANTOS, MAGNUN N. N.; KIMURA, ELZA M.; JORGE, SUSAN E. D. C.; OLIVEIRA, DENISE M.; DOMINGUES, BETANIA L. T. B.; PERES, JAQUELINE C.; ARAUJO, ADERSON S.; COSTA, FERNANDO F.; et al. Two new unstable haemoglobins leading to chronic haemolytic anaemia: Hb Caruaru [beta 122 (GH5) Phe -> Ser], a probable case of germ line mutation, and Hb Olinda [beta 22 (B4)-25 (B7)], a deletion of a 12 base-pair sequence. EUROPEAN JOURNAL OF HAEMATOLOGY, v. 83, n. 4, p. 378-382, OCT 2009. (02/13801-7)

SONATI‚ MF; KIMURA‚ EM; ABREU‚ CF; OLIVEIRA‚ DM; PINHEIRO‚ VRP; COSTA‚ FF. Hemoglobin Hammersmith [β42 (CD1) Phe→ Ser] in a Brazilian girl with congenital Heinz body hemolytic anemia. PEDIATRIC BLOOD & CANCER, v. 47, n. 6, p. 855-856, 2006. (02/13801-7)

JULIO A. DA LUZ; MÓNICA SANS; ELZA MIYUKI KIMURA; DULCINÉIA MARTINS ALBUQUERQUE; MARIA DE FATIMA SONATI; FERNANDO FERREIRA COSTA. alpha-thalassemia, HbS, and beta-globin gene cluster haplotypes in two Afro-Uruguayan sub-populations from northern and southern Uruguay. GENETICS AND MOLECULAR BIOLOGY, v. 29, n. 4, p. 595-600, 2006-00-00. (02/13801-7)

JARDIM, DENIS LEONARDO FONTES; CUNHA, ANDERSON FERREIRA DA; DUARTE, ADRIANA DA SILVA SANTOS; SANTOS, CAMILA ORESCO DOS; SAAD, SARA TEREZINHA OLALLA; COSTA, FERNANDO FERREIRA. Expression of Sara2 human gene in erythroid progenitors. Journal of Biochemistry and Molecular Biology, v. 38, n. 3, p. 328-333, May 2005. (02/13801-7)

KIMURA, ELZA M.; OLIVEIRA, DENISE M.; FERTRIN, KLEBER; PINHEIRO, VALERIA R.; JORGE, SUSAN E. D. C.; COSTA, FERNANDO F.; SONATI, MARIA DE FATIMA. Hb H disease resulting from the association of an alpha(0)-thalassemia allele [-(alpha)(20.5)] with an unstable alpha-globin variant [Hb Icaria]: First report on the occurrence in Brazil. GENETICS AND MOLECULAR BIOLOGY, v. 32, n. 4, p. 712-715, 2009. (02/13801-7)

ANDRÉ FATTORI; ELZA MIYUKI KIMURA; DULCINÉIA MARTINS DE ALBUQUERQUE; SATIE HATSUSHIKA OGO; GRAZIELA RENATA STOPPA; JULIANA TOUQUINHA MARTINS; CARMEN SILVIA PASSOS LIMA; SARA TEREZINHA OLLALA SAAD; FERNANDO FERREIRA COSTA; MARIA DE FÁTIMA SONATI. Polycythemia and Hb Coimbra [beta 99 (G1) Asp -> Glu] in Brazil. GENETICS AND MOLECULAR BIOLOGY, v. 29, n. 2, p. 200-202, 2006-00-00. (02/13801-7)

ELZA M. KIMURA; DENISE M. OLIVEIRA; KLEBER FERTRIN; VALÉRIA R. PINHEIRO; SUSAN E.D.C. JORGE; FERNANDO F. COSTA; MARIA DE FÁTIMA SONATI. Hb H disease resulting from the association of an αº-thalassemia allele [-(α)20.5] with an unstable α-globin variant [Hb Icaria]: first report on the occurrence in Brazil. GENETICS AND MOLECULAR BIOLOGY, v. 32, n. 4, p. 712-715, 2009-09-04. (02/13801-7)

WENNING, MARCIA R. S. C.; MELLO, MARICILDA P.; ANDRADE, TIAGO G.; LANARO, CAROLINA; ALBUQUERQUE, DULCINEIA M.; SAAD, SARA T. O.; COSTA, FERNANDO F.; SONATI, MARIA F.. PIP4KIIA and beta-globin: transcripts differentially expressed in reticulocytes and associated with high levels of Hb H in two siblings with Hb H disease. EUROPEAN JOURNAL OF HAEMATOLOGY, v. 83, n. 5, p. 490-493, NOV 2009. (02/13801-7)

DA LUZ, JULIO; KIMURA, ELZA MIYUKI; COSTA, FERNANDO FERREIRA; SONATI, MARIA DE FATIMA; SANS, MONICA. Beta-Globin Gene Cluster Haplotypes in Afro-Uruguayans from Two Geographical Regions (South and North). AMERICAN JOURNAL OF HUMAN BIOLOGY, v. 22, n. 1, p. 124-128, JAN-FEB 2010. (02/13801-7)

CASTILHO, L.; RIOS, M.; RODRIGUES, A.; PELLEGRINO JÚNIOR, J.; SAAD, S. T. O.; COSTA, F. F.. High frequency of partial DIIIa and DAR alleles found in sickle cell disease patients suggests increased risk of alloimmunization to RhD. Transfusion Medicine, v. 15, n. 1, p. 49-55, Feb. 2005. (02/13801-7)

DA CUNHA, ANDERSON F.; BRUGNEROTTO, ANA F.; FINZI CORAT, MARCUS A.; DEVLIN, EMILY E.; GIMENES, ANA P.; DE MELO, MONICA BARBOSA; CORREA PASSOS, LUIZ A.; BODINE, DAVID; SAAD, SARA T. O.; COSTA, FERNANDO F.. HIGH LEVELS OF HUMAN gamma-GLOBIN ARE EXPRESSED IN ADULT MICE CARRYING A TRANSGENE OF THE BRAZILIAN TYPE OF HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN ((A)gamma-195). HEMOGLOBIN, v. 33, n. 6, p. 439-447, 2009. (02/13801-7)

ROSA‚ KA; REID‚ ME; LOMAS-FRANCIS‚ C.; POWELL‚ VI; COSTA‚ FF; STINGHEN‚ ST; WATANABE‚ AM; CARBONI‚ EK; BALDON‚ JP; JUCKSCH‚ MMF; et al. Rhnull syndrome: identification of a novel mutation in RHce. Transfusion, v. 45, n. 11, p. 1796-1798, 2005. (02/13801-7)