RESUMEN
Abnormal haemoglobin (Hb) variants result in the most commonly inherited disorders in humans worldwide. In this study, we investigated the molecular epidemiology characteristics of Hb variants, along with associated structural and functional predictions in the Yunnan province population of Southwestern China. A total of 41,933 subjects who sought haemoglobinopathy screening were included. Based on bioinformatics and structural analysis, as well as protein modeling, the pathogenesis and type of Hb genetic mutations were characterized. Among all individuals studied, 328 cases (0.78%) were confirmed as carriers of Hb variants, with 13 cases (0.03%) presenting α-globin variants, 313 (0.75%) ß-globin variants, and two δ-globin variants. A total of 19 different mutations were identified, including three novel mutations. In addition, 48 cases of ααCS mutations and 14 cases of Hb H or Hb Bart's were found. The isoelectric point, evolutionary conservation, and genotype-phenotype correlation for these mutations were predicted. Additionally, secondary and tertiary protein structure modeling were performed for three selected mutations. In conclusion, the prevalence of Hb variants in the Yunnan population is much higher than other regions of China. Complete characterization of these Hb variants is essential for generating a rational strategy to control the haemoglobinopathies in this region.
Asunto(s)
Hemoglobinopatías/epidemiología , Hemoglobinopatías/genética , Hemoglobinas Anormales/genética , Epidemiología Molecular , Adolescente , Adulto , Niño , Preescolar , China/epidemiología , Biología Computacional , Femenino , Genotipo , Hemoglobinopatías/sangre , Hemoglobinas Anormales/ultraestructura , Heterocigoto , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Adulto Joven , Globinas alfa/genética , Talasemia alfa/sangre , Talasemia alfa/epidemiología , Talasemia alfa/genética , Globinas beta/genética , Talasemia beta/sangre , Talasemia beta/genética , Talasemia beta/patología , Globinas delta/genéticaRESUMEN
Hemoglobin variants in which a frameshift results in chain elongation are unusual. Hemoglobin Pakse (Hb Pakse) is an unstable hemoglobin with abnormal elongation, first described in Indochina. An alpha2-globin gene termination codon mutation, TAA -->TAT or Term -->Tyr, has been described in the pathogenesis of Hb Pakse. This abnormality causes a frameshift that elongates the alpha chain amino acids. Computer-based protein structure modeling was used in a bioinformatics analysis of the tertiary structure of these elongated amino acid sequences. The elongated part of Hb Pakse showed additional helices, which may cause the main alteration in Hb Pakse. Abnormalities in the fold structure of globin in Hb Pakse were identified, and helices additional to the normal alpha globin chains were shown in the elongated part of Hb Pakse.
Asunto(s)
Hemoglobinas Anormales/química , Hemoglobinas Anormales/ultraestructura , Modelos Químicos , Modelos Moleculares , Análisis de Secuencia de Proteína/métodos , Secuencia de Aminoácidos , Simulación por Computador , Datos de Secuencia Molecular , Mutación , Conformación Proteica , Estructura Secundaria de ProteínaRESUMEN
Several alpha-chain hemoglobin variants have been described as responsible, in homozygous or compound heterozygous patients, for a chronic hemolytic disease that overlaps thalassemia and Heinz bodies hemolytic anemia phenotypes. These variants are present in trace amounts together with some Hb H in the lysate of the patients. In the asymptomatic heterozygous carriers, they are usually not detected by electrophoretic methods. Hb Taybe is an example of such an unstable and thalassemic alpha-hemoglobin variant. This hemoglobin was observed in a young Israeli Arab woman having suffered since birth from a severe and highly regenerative hemolytic anemia for which she was splenectomized at age sixteen. The structural abnormality was characterized by protein chemistry as the deletion of a threonine residue at position alpha 38 or 39 and assigned to the alpha 1 gene by selective DNA sequencing. This structural modification is localized in helix C, which is a highly conserved 3(10) helix participating in the alpha 1 beta 2 contact and close to the alpha 1 beta 1 interface. The propositus and two siblings, who were also anemic, were found to be homozygous for the molecular defect, although the abnormal Hb was not detected in the latters. Consanguinity in this family demonstrated the threshold effect in the clinical manifestations of such alpha-gene disorders since heterozygotes were clinically and biologically normal.
Asunto(s)
Anemia Hemolítica Congénita/sangre , Globinas/ultraestructura , Hemoglobinas Anormales/genética , Adulto , Femenino , Hemoglobinas Anormales/ultraestructura , Homocigoto , Humanos , Linaje , Reacción en Cadena de la PolimerasaRESUMEN
The structures of carbonmonoxyhaemoglobins A and Cowtown (His146 beta----Leu) have been refined at 2.2 A (1 A = 0.1 nm) and 2.3 A resolution, respectively. The least squares fit to the Fe-C-O line makes an angle to the haem normal of about 6 degrees. The Fe-C-O group is bent from linearity by about 7 degrees. The porphyrins in the CO liganded haemoglobins are ruffled. This deformation of the haem and the distortion of the Fe-C-O group may explain the low CO affinity of haemoglobin. The electron density for the C-terminal residues is low but sufficient to distinguish the histidyl and leucyl residues clearly. The similarity between these two structures, apart from 146 beta, means that the reduced alkaline Bohr effect is due solely to the replacement of histidine by a leucine.
