Evidence for multiple structural genes for the gamma chain of human fetal hemoglobin.

Schroeder, W. A.; Huisman, T. H. J.; Shelton, J. R.; Shelton, J. C.; Kleihauer, E.; Dozy, Andrée M.; Robberson, Barbara

doi:10.1073/pnas.60.2.537

Cited by 308 publications

(93 citation statements)

References 22 publications

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“…It is, however, possible that 6, 'y, and other globin genes are also being measured. The precise number of each of these genes is unknown in humans; however, at least two, and perhaps more, -y genes are present in haploid human genomes (18). In addition, untrauiscribed globin genes may be present; for example, so-called minor, multiple 6 globin genes have been reported in apes (19).…”

Section: Resultsmentioning

confidence: 99%

A Limited Number of Globin Genes in Human DNA

Gambino

Kacian

O'Donnell

et al. 1974

Proc. Natl. Acad. Sci. U.S.A.

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The number of globin genes in human cells was determined by hybridizing DNA from human spleens to 3H-labeled DNA complementary to human globin mRNA. Assuming the rates of reannealing of complementary DNA and cellular DNA are similar, the extent of hybridization of complementary DNA at various ratios of cellular DNA to complementary DNA indicate that there are fewer than 10 globin gene copies per haploid human genome. An alternative analysis of the data, which introduces no assumptions concerning the relative rates of reaction of complementary DNA and cellular DNA, indicates fewer than 20 globin gene copies are present. DNA isolated from the spleen of a patient with ( + thalassemia contained a number of globin gene copies similar to that of normal DNA.The mechanisms regulating human hemoglobin synthesis at the gene level are poorly understood. Since both transcriptional and translational controls may be involved, it is of importance to determine the number of globin genes in man. The availability of highly radioactive DNA (cDNA) complementary to globin mRNA (1-3) provides a useful tool for this purpose. Recent reports of the use of mouse liver and duck reticulocytes indicate that there are fewer than 10 copies of the globin sequences present per haploid genome (4-6). In addition, the number of globin genes present in duck reticulocytes and liver cells has been found to be similar (4). The experiments reported here were undertaken to measure the number of globin genes present in human genomes, and to compare the number of genes in the cells of patients with B+ thalassemia and without thalassemia. Human cDNA was used to probe DNA from human spleens for the number of globin gene copies. The results are consistent with genetic evidence, and indicate that fewer than 20 globin genes are present in normal haploid human genomes. In addition, there is no detectable difference in the number of globin genes present in DNA from the cells of a patient with (3+ thalassemia. METHODSPreparation and Characterization of Human DNA. Human DNA was isolated from individual spleens of patients with and without thalassemia obtained when splenectomy was indicated for treatment of the patient. The spleens were collected within 1 hr after surgery, cut into small pieces, frozen immediately in liquid nitrogen, and stored at -70°. The spleens were ground to a coarse powder in a mortar cooled with dry ice, and the DNA was isolated by the following procedure modified from those reported (7, 8): Frozen spleen powder (10-50 g) was suspended at 40 in 5% sucrose buffer containing 1 mM MgCl2 and 1 mM NaH2PO4 (pH 6.5). The cells were broken by 25 strokes in a tight-fitting Dounce homogenizer. The nuclei were separated by centrifugation at 800 X g for 10 min, washed once with the 5% sucrose solution, and taken up in 10-20 volumes of 10 mM Tris (pH 8.3), 0.15 M NaCl, 5 mM EDTA, 1% sodium dodecyl sulfate, 1.0 M NaClO4.After addition of an equal volume of CHCl3-isoamyl alcohol (24: 1), the mixture was shaken for 30 min at room temperature. The aq...

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Section: Resultsmentioning

confidence: 99%

A Limited Number of Globin Genes in Human DNA

Gambino

Kacian

O'Donnell

et al. 1974

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent studies by SCHROEDER et al [42] have offered evidence for the structural heterogeneity of human fetal hemoglobin. I t seems that at least two (and possibly more) types of y polypeptide chains are synthesized in the normal human fetus; these y chains differ at a minimum in one residue, namely, residue 136, which is occupied either by a glycyl or a n alanyl residue.…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin C in Newborn Sheep and Goats: A Possible Explanation for its Function and Biosynthesis

et al. 1969

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“…In that only a sub-population of clones in the phage display were sequenced and identified, we did not determine if other globin chains besides the gamma (A) chain also bound to Aβ using this approach. However, the coding regions of HBG1 and HBG2, that code for the gamma (A) and gamma (G) globin chains of Hb F, respectively, exhibit a high degree of homology differing only by a single base pair [86]. Therefore, it is likely that the gamma (G)-globin chain binds Aβ with the same high avidity as the gamma (A) chain.…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

Perry

Gearhart

Wiener

et al. 2008

Neurobiology of Aging

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From a normal human brain phage display library screen we identified the gamma (A)-globin chain of fetal hemoglobin (Hb F) as a protein that bound strongly to Aβ1-42. We showed the oxidized form 1 These authors are co-corresponding authors for all stages of refereeing and publication and contributed equally to this work. Rodney T. Perry; Rm. 210H, 1665 University Blvd.; University of Alabama at Birmingham, Birmingham, USA; Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure Statement:I so state for myself and on behalf of the other authors on the manuscript, Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease, that we have no conflicts and sources of funding that influence the results of this paper, the data is not published or submitted elsewhere, and that appropriate approval and procedures were used concerning human subjects. I also verify that all authors on this manuscript have reviewed the contents of the manuscript, approve of its contents, and validate the accuracy of the data. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of adult Hb (metHb A) binds with greater affinity to Aβ1-42 than metHb F. MetHb is more toxic than oxyhemoglobin because it loses its heme group more readily. Free Hb and heme readily damage vascular endothelial cells similar to Alzheimer's disease (AD) vascular pathology. The XmnI polymorphism (C→T) at −158 of the gamma (G)-globin promoter region can contribute to increased Hb F expression. Using family-based association testing, we found a significant protective association of this polymorphism in the NIMH sibling dataset (n=489) in families, with at least two affected and one unaffected sibling (p=0.006), with an age of onset >50 years (p=0.010) and >65 years (p=0.013), and families not homozygous for the APOE4 allele (p=0.041). We hypothesize that Hb F may be less toxic than adult Hb in its interaction with Aβ and may protect against the development of AD.

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Evidence for multiple structural genes for the gamma chain of human fetal hemoglobin.

Cited by 308 publications

References 22 publications

A Limited Number of Globin Genes in Human DNA

A Limited Number of Globin Genes in Human DNA

Hemoglobin C in Newborn Sheep and Goats: A Possible Explanation for its Function and Biosynthesis

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

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