RESUMO
High altitude exerts selective evolutionary pressure primarily due to its hypoxic environment, resulting in multiple adaptive responses. High hemoglobin-oxygen affinity is postulated to be one such adaptive change, which has been reported in Sherpas of the Himalayas. Tibetans have lived on the Qinghai-Tibetan plateau for thousands of years and have developed unique phenotypes, such as protection from polycythemia which has been linked to PDH2 mutation, resulting in the downregulation of the HIF pathway. In order to see if Tibetans also developed high hemoglobin-oxygen affinity as a part of their genetic adaptation, we conducted this study assessing hemoglobin-oxygen affinity and their fetal hemoglobin levels in Tibetan subjects from 3 different altitudes. We found normal hemoglobin-oxygen affinity in all subjects, fetal hemoglobin levels were normal in all except one and no hemoglobin variants in any of the subjects. We conclude that increased hemoglobin-oxygen affinity or increased fetal hemoglobin are not adaptive phenotypes of the Tibetan highlanders.
Assuntos
Adaptação Biológica/genética , Altitude , Adulto , Idoso , Povo Asiático/genética , Feminino , Hemoglobinas/metabolismo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Oximetria , Oxigênio/metabolismo , Ligação Proteica , Tibet , Estados UnidosAssuntos
Hemoglobinas Anormais/genética , Reação em Cadeia da Polimerase/métodos , Talassemia beta/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 16/genética , Genótipo , Humanos , Lactente , Pessoa de Meia-Idade , Adulto Jovem , alfa-Globinas/genética , Globinas beta/genética , Talassemia beta/diagnóstico , Globinas delta/genética , Talassemia delta/diagnóstico , Talassemia delta/genéticaRESUMO
Sickle cell disease (SCD) is a classic example of a disorder with recessive Mendelian inheritance, in which each parent contributes one mutant allele to an affected offspring. However, there are exceptions to that rule. We describe here the first reported case of conversion of inherited sickle cell trait to SCD by uniparental disomy (UPD) resulting in mosaicism for SS and AS erythrocytes. A 14-year-old boy presented with splenomegaly and hemolysis. Although his father has sickle cell trait, his mother has no abnormal hemoglobin (Hb). DNA sequencing, performed to rule out Hb S/ß-thalassemia, detected homozygous Hb SS. Further studies revealed mosaic UPD of the ß-globin locus, more SS erythroid progenitors than AS, but a reverse ratio of erythrocytes resulting from the survival advantage of AS erythrocytes. This report exemplifies non-Mendelian genetics wherein a patient who inherited sickle cell trait has mild SCD resulting from postzygotic mitotic recombination leading to UPD.
Assuntos
Anemia Falciforme/genética , Traço Falciforme/genética , Dissomia Uniparental , Adolescente , Anemia Falciforme/sangue , Sequência de Bases , Cromossomos Humanos Par 11/genética , Análise Mutacional de DNA , Eritrócitos/metabolismo , Células Precursoras Eritroides/metabolismo , Feminino , Hemoglobina A/metabolismo , Hemoglobina Falciforme/metabolismo , Humanos , Perda de Heterozigosidade , Masculino , Mitose/genética , Mosaicismo , Mutação Puntual , Traço Falciforme/sangue , Globinas beta/genéticaRESUMO
Two polycythemic subjects from a family with multiple polycythemic subjects were evaluated. Estimation of oxygen affinity of Hb from venous blood gas parameters (P50) revealed low P50 suggesting a high affinity Hb variant. Further work up, which included beta globin gene sequencing, revealed a novel mutation changing a codon to the previously reported high affinity Hb - Hb Johnstown (beta 109 Val->Leu). Polycythemic subjects with high affinity Hb variant are asymptomatic with normal life expectancy. Their differentiation from polycythemia vera (PV) is crucial to avoid therapy which is otherwise reserved for PV patients. We provide an electronic version (in Microsoft excel program) of a previously reported mathematical formula for rapid calculation of P50 from venous blood gases. Estimation of P50 is an essential initial step in the evaluation of a subject with personal and family history of polycythemia.
