Bases moleculares de alfa-talasemia en la Argentina

La α-talasemia, es uno de los desórdenes hereditarios más frecuentes mundialmente. Al presente, el diagnóstico molecular es la única herramienta que permite el diagnóstico certero. El propósito de este trabajo fue caracterizar las bases moleculares de estos síndromes en nuestro medio, y establecer relaciones genotipo-fenotipo. Mediante la complementación de distintas técnicas de biología molecular e hibridación fluorescente in situ (FISH), se logró poner en evidencia la presencia de mutaciones α-talasémicas en 145 de 184 (78.8%) pacientes estudiados con perfil hematológico compatible con α-talasemia. Dentro de este grupo, las deleciones correspondieron al defecto genético más frecuente, prevaleciendo la mutación -α3.7 en genotipos heterocigotas y homocigotas. Asimismo, en pacientes con fenotipo α0 las deleciones prevalentes fueron -MED y -CAL/CAMP. Este estudio permitió también describir una deleción de la región sub-telomérica en un paciente con α-talasemia y retraso mental. En el 7.6% de los pacientes caracterizados clínicamente como posibles α-talasémicos (microcitosis con valores de Hb A2 inferiores al 3.5%), se hallaron mutaciones β-talasémicas en estado heterocigota. Se lograron establecer perfiles hematológicos asociados a los genotipos α+ y α0 para pacientes adultos y niños. Esperamos que este trabajo pueda servir como guía para reconocer posibles portadores α-talasémicos. También permite destacar el trabajo en conjunto de médicos hematólogos, el laboratorio (bioquímico y de biología molecular) y de los médicos genetistas, con el fin de proporcionar adecuado consejo genético.

The α-thalassemia is one of the most common hereditary disorders worldwide. Currently, molecular diagnostics is the only available tool to achieve an accurate diagnosis. The purpose of this study was to characterize the molecular bases of these syndromes in our environment and to establish genotype-phenotype associations. Through a combination of different molecular techniques and fluorescent in situ hybridization (FISH),we were able to find α-thalassemic mutations in 145 of the 184 patients (78.8%) studied with hematological parameters compatible with α-thalassemia. Deletions of the a-globin genes resulted the major molecular cause of the disease, and the most frequent mutation was -α3.7, found in homozygous and heterozygous genotypes. In patients with α0 phenotypes, other prevalent mutations were -MED and -CAL/CAMP. The description of a sub-telomeric deletion in a patient with α-thalassemia and mental retardation was also achieved. β-thalassemic mutations in heterozygous state were found in 7.6% of the patients, who presented α-thalassemic clinical features (microcytosis and Hb A2 levels below 3.5%). Hematologic profiles for the α+ and α0 genotypes were established for adult and pediatric patients. Hopefully, this work will provide guidelines for the detection of possible α-thalassemic carriers. It also highlights the collaborative work of hematologists, the biochemical and molecular biology laboratory and genetists, in order to provide appropriate genetic counseling.

Molecular studies on Yemeni sickle-cell-disease patients: Xmn I polymorphism

Our studies of the Saudi population have shown that in patients with mild presentation of sickle-cell disease [SCD] from Saudi Arabia's eastern region, the prevalence of polymorphic sites is high. However, the prevalence is very low in patients with severe SCD from the south-west of the country. We expanded these studies to a group of Yemeni patients with severe SCD, resident in Riyadh. We investigated a total of 60 chromosomes carrying the sickle-cell [Hb S] gene and 14 chromosomes carrying the Hb A gene. Amongst the Hb AA group, the prevalence was 42.9% and 57.1% for the presence [+] and absence [-] of Xmn I polymorphic sites. In the Hb SS individuals, the prevalence of Xmn I polymorphic sites was similar to the prevalence reported in the south-western region of Saudi Arabia

Molecular analysis of the human fetal-to-adult globin switching.

Hereditary persistence of fetal hemoglobin (HPFH) is a condition characterized by continued expression of the gamma-globin gene in adult life. Analysis of a Japanese HPFH family had revealed that the C-T transition at position -114 within the distal CCAAT box of the gamma-globin gene associated with the HPFH allele. In the vicinity of the distal CCAAT box, other two mutations (-117 C-T, 13 bp del) had been identified in individuals with a HPFH phenotype. Functional analysis of these mutant promoters in erythroid cell lines suggested that the distal CCAAT box works positively in the fetus but negatively in the adult on the expression of the gamma-globin gene. Further study on transgenic mice showed that the -114 mutation was responsible for the elevated expression of the gamma-globin gene in the adult. To elucidate the molecular mechanism underlying the persistent expression of the gamma-globin genes associated with the HPFH mutations, interaction of the mutant promoters with nuclear factors was analyzed. Relevance of the nuclear factor, NFE3, to the gamma-globin regulation was suggested by the affected binding of NFE3 to the altered distal CCAAT boxes with HPFH mutations (-117, -114, 13 bp del).

A case of homozygous sickle cell disease in Sri Lanka.

An 11 year old Muslim boy with a 2 month history of fever, loss of appetite, pallor and abdominal distension, had hepato-splenomegaly. Haemoglobin electrophoresis showed the presence of haemoglobins S and F, with complete absence of haemoglobin A. The sickling test was positive. Marital consanguinity was present. In both parents, the sickling test was positive and haemoglobin electrophoresis showed the presence of haemoglobins A and S. This is the first report of homozygous sickle cell disease in Sri Lanka.

Haemoglobin E and A2 in agricultural and migratory populations of West Bengal. A preliminary report.

A total of 424 blood samples were collected from two distinct populations. Local agricultural group and migratory industrial workers of West Bengal were compared with respect to haemoglobin, ABO and Rh systems. There was absence of any significant genetic difference in case of haemoglobin system.

Estigma para hemoglobina S e hemoglobina fetal / Stigma for hemoglobin S and fetal hemoglobin

Säo analisados os resultados de hemoglobina fetal apresentados por 112 indivíduos com estigma para hemoglobina S e comparados com os resultados de hemoglobina fetal encontrados em 112 indivíduos com homozigose para hemoglobina A. Os estigmas para hemoglobina S foram pareados com os homozigotos de hemoglobina A através do sexo, idade, dosagem de hemoglobina total e hematócrito. A hemoglobina fetal com valores elevados (acima de 1,3%) somente foi encontrada naqueles que possuíam a seguinte associaçäo: estigma para hemoglobina S e dosagem de hemoglobina total igual ou acima de 13,7 g/100 ml para os homens e 12,4 g/100 ml para as mulheres