RESUMEN
This study refers to the quantitative hemoglobin (Hb) phenotype of a 19-year-old female with Hb Valletta [beta87(F3)Thr-->Pro] in association with Hb Marseille/Long Island [beta2(NA2)His-->Pro; (-1)Met-(+1)Val-(+2)Pro-Leu] and a normal Hb electrophoretogram. The data serve to alert investigators to the possibility that relatives with apparently normal Hb phenotypes may be transmitting mutant alleles and suggest methods for identification.
Asunto(s)
Hemoglobinas Anormales/genética , Complicaciones Hematológicas del Embarazo/genética , Globinas beta/genética , Transfusión Sanguínea , Inglaterra/etnología , Femenino , Hemorragia/etiología , Hemorragia/terapia , Heterocigoto , Humanos , Recién Nacido , Masculino , Malta , Persona de Mediana Edad , Linaje , Fenotipo , Embarazo , Complicaciones Hematológicas del Embarazo/terapia , Adulto JovenRESUMEN
Hereditary persistence of fetal hemoglobin (HPFH) is characterized by persistent high levels of fetal hemoglobin (HbF) in adults. Several contributory factors, both genetic and environmental, have been identified but others remain elusive. HPFH was found in 10 of 27 members from a Maltese family. We used a genome-wide SNP scan followed by linkage analysis to identify a candidate region on chromosome 19p13.12-13. Sequencing revealed a nonsense mutation in the KLF1 gene, p.K288X, which ablated the DNA-binding domain of this key erythroid transcriptional regulator. Only family members with HPFH were heterozygous carriers of this mutation. Expression profiling on primary erythroid progenitors showed that KLF1 target genes were downregulated in samples from individuals with HPFH. Functional assays suggested that, in addition to its established role in regulating adult globin expression, KLF1 is a key activator of the BCL11A gene, which encodes a suppressor of HbF expression. These observations provide a rationale for the effects of KLF1 haploinsufficiency on HbF levels.
Asunto(s)
Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Adulto , Células Cultivadas , Eritropoyesis/genética , Familia , Femenino , Regulación del Desarrollo de la Expresión Génica/genética , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/metabolismo , Humanos , Pérdida de Heterocigocidad/fisiología , Masculino , Linaje , Factores de Transcripción/genética , TransfecciónRESUMEN
The biosynthesis of Hb F in place of the deficient Hb A could be a suitable treatment for beta hemoglobinopathies. Among newborn Hb F-Malta-I heterozygotes, it could be shown that the XmnI sequence alone had little, if any effect on gamma-globin gene expression, but interplay with the (AT)(X)T(Y) sites in cis and in trans may occur. In contrast, while the XmnI sequence is clearly correlated with gamma-globin levels in anemic adult beta-thalassemia (thal) homozygotes, the effect on F-erythrocyte numbers and Hb F/F-erythrocyte appears independent of the (AT)(X)T(Y) sites. Even at levels of hydroxyurea (HU) as low as 1.65 mg/kg/day (vs. 10 mg/kg/day on the high dose regime) it can be shown that although even a small increase of Hb F could be obtained, the effect was rarely translated into an increase in circulating hemoglobin (Hb). In most cases, the elevated Hb F level was dependent on the XmnI sequence and was due to increased numbers of F-erythrocytes or Hb F/F-erythrocyte or both. It seems that the bone marrow of thalassemia homozygotes may be more sensitive to myelosuppression by HU possibly due to medullary inflammation. While the data are consistent with loop models of globin switching mechanisms, there is urgent need for large, hypothesis driven, multicenter trials of molecules that could maintain or re-induce high Hb F levels in beta-thal and subject to genetic and epigenetic constraints including inflammation.