Proportion of hemoglobin G Philadelphia (alpha 268 Asn leads to Lys beta 2) in heterozygotes is determined by alpha-globin gene deletions.
AUTOR(ES)
Sancar, G B
RESUMO
In humans the alpha-globin genes are duplicated and closely linked. Whereas individuals heterozygous for most alpha-chain mutations possess approximately 25% abnormal hemoglobin, heterozygotes for the alpha-chain variant Hb G Philadelphia synthesize either 33% or 50% Hb G. Both variable gene dosage and interaction with alpha-thalassemia have been proposed to explain this observation. To differentiate between these models, we have performed restriction endonuclease mapping and hematological studies on individuals with Hb G from four families. In every case the alpha G locus was carried on an EcoRI or EcoRI + BamHI fragment approximately 4 kilobases shorter than that bearing the two linked alpha A loci of hematologically normal individuals. Bgl II digestion revealed that the alpha G gene is the only alpha locus on the affected chromosome. Erythrocyte indices and alpha/beta synthesis ratios indicated that the alpha G chromosome confers alpha-thalassemia. In addition to the alpha G gene, subjects who synthesized 33% Hb G possessed two alpha A genes on the homologous chromosome and exhibited the mild form of alpha-thalassemia trait ("silent carrier"). Subjects who synthesized 50% Hb G possessed a single alpha A gene trans to the alpha G locus and displayed the more pronounced form of alpha-thalassemia trait. One subject, who synthesized 100% alpha G chains and had Hb G-Hb H disease, was found to have a single nonfunctional alpha gene trans to the alpha G gene. Thus the proportion of Hb G synthesized by heterozygotes is determined by interaction with alpha-globin gene deletions cis and trans to the alpha G locus.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=350393Documentos Relacionados
- Deletions in the alpha-globin gene complex in alpha-thalassemic mice.
- Inactivation of human alpha-globin gene expression by a de novo deletion located upstream of the alpha-globin gene cluster.
- Molecular analysis of the beta-thalassemia phenotype associated with inheritance of hemoglobin E (alpha 2 beta2(26)Glu leads to Lys).
- DNA methylation in chicken alpha-globin gene expression.
- Non-methylated CpG-rich islands at the human alpha-globin locus: implications for evolution of the alpha-globin pseudogene.