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

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)