ABSTRACT
Durante el desarrollo de un individuo se expresan distintas cadenas de globina de tipo a y no-a, que se combinan en tetrámeros para formar hemoglobina. Los genes que las codifican se organizan en familias. Distintas mutaciones afectan los genes que codifican las cadenas de globina: si provocan alteraciones cualitativas originan cuadros de hemoglobinopatías estructurales, si disminuyen las síntesis de las cadenas de globina, talasemias, y si tienen ambos efectos, hemoglobinopatías talasémicas. El propósito de este trabajo es presentar las bases moleculares de las hemoglobinopatías en Argentina, en un total de 862 muestras, en base a los estudios moleculares realizados en este laboratorio a partir del estudio de 910 muestras de pacientes. En nuestro medio, la Hb S es la hemoglobinopatía estructural más frecuente, las ß-talasemias presentan una distribución similar a la cuenca del Mediterráneo y las a-talasemias están intrínsecamente relacionadas a la ascendencia de los afectados. Las bases moleculares de las hemoglobinopatías son variadas. Mientras que en las hemoglobinopatías estructurales y ß-talasemias predominan las mutaciones puntuales, en las a-talasemias predominan las deleciones. Se describen mutaciones nóveles (cambios puntuales, deleciones y duplicaciones) que se presentan como eventos aislados con herencia recesiva o dominante. Es necesaria la interacción entre el médico hematólogo, el laboratorio bioquímico, el laboratorio molecular y el médico genetista, para llegar al diagnóstico certero de estos cuadros que permitirán reducir la incidencia de las formas severas.
Functional hemoglobin is a tetramer composed of 2 a and 2 non-a chains, encoded by genes that are organized in clusters and are expressed sequentially through development. There are multiple mutations described that affect these genes: if the sequence variant leads to a qualitative alteration, the resulting effect is a structural hemoglobinopathy, if it decreases the synthesis of the globin chains, thalassemia, and if it affects both the quality and quantity of the globin chain, the consequence is a thalassemic hemoglobinopathy. The aim of this paper is to present the molecular bases of hemoglobinopathies in Argentina, determined in 862 patients, based on the results of the molecular studies carried out in our laboratory from the analysis of 910 samples. Hb S is the most frequent structural hemoglobinopathy, ß-thalassemia mutations exhibit a pattern similar to the one displayed by Mediterranean basin populations, and a-thalassemia mutations are intrinsically related to the ancestry of those affected. These syndromes exhibit diverse molecular bases: structural hemoglobinopathies and ß-thalassemia are a consequence, mostly of point mutations, whereas in a-thalassemia deletions prevail. Novel mutations (point changes, deletions and duplications) that occurred as isolated events, with recessive or dominant inheritance, were described. Interaction between the hematologist, the geneticist and both the clinical and molecular biology laboratories is necessary to reach an accurate diagnosis of these syndromes and reduce the incidence of severe forms.
Durante o desenvolvimento de um indivíduo expressam-se diversas cadeias de globina de tipo a e não-a, que se combinam em tetrámeros para formar hemoglobina. Os genes que as codificam são organizados em famílias. Diferentes mutações afetam os genes que codificam as cadeias de globina: se provocarem alterações qualitativas originam quadros de hemoglobinopatias estruturais, se diminuírem as sínteses das cadeias de globina, talassemias, e se tiverem ambos os efeitos, hemoglobinopatias talassêmicas. O propósito deste trabalho é apresentar as bases moleculares das hemoglobinopatias na Argentina, num total de 862 amostras, com base nos estudos moleculares realizados neste laboratório a partir do estudo de 910 amostras de pacientes. No nosso meio, a Hb S é a hemoglobinopatia estrutural mais frequente, as ß-talassemias apresentam uma distribuição similar à bacia do Mediterrâneo e as a-talassemias estão intrinsecamente relacionadas com a ascendência dos afetados. As bases moleculares das hemoglobinopatias são variadas. Enquanto nas hemoglobinopatias estruturais e ß-talassemias predominam as mutações pontuais, nas a-talassemias predominam as deleções. Descrevem-se mutações incipientes (mudanças pontuais, deleções e duplicações) que se apresentam como eventos isolados com herança recessiva ou dominante. É necessária a interação entre o médico hematólogo, o laboratório bioquímico, o laboratório molecular e o médico geneticista, para chegar ao diagnóstico certo desses quadros que permitirão reduzir a incidência das formas severas.
Subject(s)
Humans , Hemoglobins/analysis , Hemoglobinopathies , Hemoglobinopathies/diagnosis , Argentina , Thalassemia , HemoglobinsABSTRACT
Las a talasemias en la mayoría de los casos es debida a deleciones que afectan a uno o a los dos genes a, siendo poco frecuente los casos debidos a mutaciones puntuales, inserciones o deleciones de pocos pares de bases, los cuales se han denominado a talasemias no deleción. Se determinó la incidencia de la a talasemia no deleción en los pacientes con a talasemia, mediante biología molecular. Se estudiaron 517 individuos remitidos al Hospital Clínico San Carlos, centro de referencia de estudios moleculares de Talasemias en Madrid- España, entre Enero del 2001 a Diciembre del 2003, en los que se había descartado ferropenia y presentaban microcitosis, hipocromía, Hb A2, Hb F y EEF de Hbs normales. Se estudiaron los 2 tipos de a talasemia no deleción más descritas en el Mediterráneo: 1) aHph debida a la deleción de 5 bp en el IVS I y 2) aNco a un cambio en el codón de iniciación del gen. De los 517, 40 presentaban una a talasemia no deleción (7,7%). De éstos, 28 fueron positivos para aHph del gen a2, 24 en estado heterocigoto, 1 homocigoto y 3 dobles heterocigotos asociados con la deleción 3,7 kb. Los 12 restantes resultaron positivos para la aNco del gen a2, 10 heterocigotos, 1 homocigoto y 1 doble heterocigoto asociado con la deleción 4,2 kb. La a talasemia no deleción representa < 8% de los casos de a talasemia en nuestro medio. La aHph es el tipo de a talasemia no deleción más frecuente y cuyas anormalidades hematológicas son más manifiestas que las presentadas en los casos de aNco.
The a thalassaemia diseases in most cases are caused by deletions that affect one or two of the a genes, being less frequent the cases due to punctual mutations, insertions or deletions of a few pairs of bases, which have been denominated no deletion a thalassaemias. The objective of this investigation was to determine the incidence of the no deletion a thalassaemia in patients with a thalassaemia using molecular biology techniques. We studied 517 individuals of the San Carlos Hospital (Thalassemia Molecular Research Center, Madrid-Spain) between January 2001 and December 2003, in whom iron deficiency anemia had been ruled out, that presented microcytosis and hypochromia and that presented normal HbA2, HbF and EEF from normal Hbs. The two types of no deletion a thalassaemia most frequently described in the Mediterranean were studied: 1) a Hph due to deletion of 5bp in the IVS I and 2) aNco due to a change in the initiation codon of the gene. Of the 517 cases studied, 40 (7.7% of the cases) represented a no deletion a thalassaemia. Of these cases, 28 were positive for aHph of the a2 gene, 24 in the heterozygote state, one homozygote and three double heterozygotes associated with the 3,7 kb deletion. The remaining 12 cases were positive for the aNco of the a2 gene, 10 heterozygotes, one homozygote and one double heterozygote associated with the 4,2 kb deletion. The no deletion a thalassaemias represent < 8% from the cases in our environment. The aHph is the most frequent type of no deletion a thalassaemia and its haematological abnormalities are more manifest that the ones present in the cases of aNco.