Assuntos
Anemia Falciforme/genética , Cistationina beta-Sintase/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Protrombina/genética , Trombofilia/genética , Trombose/epidemiologia , Regiões 3' não Traduzidas/genética , Adulto , Alelos , Anemia Falciforme/epidemiologia , Criança , Estudos de Coortes , Cistationina beta-Sintase/fisiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Guadalupe/epidemiologia , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/fisiologia , Prevalência , Protrombina/fisiologia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/genética , Trombose/etiologia , Trombose/genéticaRESUMO
Hb Montefiore was found, in the heterozygous state, in a Puerto Rican female who had a slightly elevated total Hb level. Structural analysis revealed that Asp-alpha126 was replaced by Tyr. Hb Montefiore migrates close to HbF (at pH 8.6) and accounts for 20.3% of the hemolysate. Oxygen binding of red blood cells revealed a 40% decrease in the P50 (pH 7.4) and a low n value of 1.6 (normal: 2.6). Depletion of red blood cell 2,3-DPG did not change the results. Stripped Hb Montefiore at pH 7.2 showed an 8-fold reduction in P50 (0.6 versus 4.6 mm Hg) and very low cooperativity (n = 1.2 versus 2.9 for the control). Heterotopic effectors, as 2,3-diphosphoglycerate and inositol hexaphosphate had a normal effect and in addition, they increased cooperativity. The chloride ion effect and the Bohr effect were moderately reduced. A bezafibrate derivative (L345), known to bind alpha126, increases the P50 of HbA by 9-fold, but only by 1. 5-fold that of Hb Montefiore. Combining these functional studies with intrinsic fluorescence and Resonance Raman spectroscopy, we interpret the very low n value and the high oxygen affinity for Hb Montefiore as a result of both a destabilized T state that switches to R upon ligand binding and a deoxy T state that binds ligands with higher affinity than that of deoxy HbA. Hb Montefiore still binds ligands cooperatively, but the difference in ligand binding properties of the two quaternary states has been drastically reduced.
Assuntos
Hemoglobinas Anormais/química , Hemoglobinas Anormais/genética , Hemoglobinas Anormais/metabolismo , Mutação , Oxigênio/metabolismo , Regulação Alostérica , Ácido Aspártico/genética , Cromatografia Líquida de Alta Pressão , Eritrócitos/metabolismo , Feminino , Heterozigoto , Humanos , Recém-Nascido , Porto Rico/etnologia , Espectrometria de Fluorescência , Análise Espectral Raman , Tirosina/genéticaAssuntos
Anemia Falciforme/genética , Epistasia Genética , Frequência do Gene , Globinas/genética , Talassemia alfa/genética , Adolescente , Adulto , Distribuição por Idade , Idoso , Anemia Falciforme/epidemiologia , Criança , Pré-Escolar , Comorbidade , Cuba/epidemiologia , Feminino , Genótipo , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Talassemia alfa/epidemiologiaRESUMO
We have studied 91 patients with SS genotype, 44 children and 47 adults. Excluding the Cameroon and atypical haplotypes, the distribution in the children's sample exhibited 43% Benin, 38% Bantu, and 3% Senegal. In adults, the sample exhibited 46% Benin, 30% Bantu, and 9% Senegal (chi 2: 13.511, 2 df, P = 0.001). When the whole sample of 198 chromosomes (SS, SC, and S/beta thal) is considered, we find that the beta s chromosome is linked 51% to the Benin haplotype, 41% with the Bantu, and 8% with the Senegal. After adjusting for the different frequencies of beta s in Africa, these numbers would predict the port of origin to be 16% from Atlantic West Africa, 37.3% from Central West Africa, and 46% from Bantu-speaking Africa. This is in direct contradiction with the historical record that establishes a higher percentage from Bantu-speaking Africa (55%) and a much lower percentage from Senegal (3.4%). The overall conclusions from these findings is that there is a loss of Bantu haplotypes in sickle cell syndromes in Cuba, particularly among adults, and that there is an excess of Senegal haplotype, also among adults. These differences might reflect the differential survival and severity of the sickle cell disease linked to these haplotypes.