RGD Reference Report - A human embryonic hemoglobin inhibits Hb S polymerization in vitro and restores a normal phenotype to mouse models of sickle cell disease. - Rat Genome Database

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A human embryonic hemoglobin inhibits Hb S polymerization in vitro and restores a normal phenotype to mouse models of sickle cell disease.

Authors: He, Z  Russell, JE 
Citation: He Z and Russell JE, Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10635-40. Epub 2002 Jul 17.
RGD ID: 11353858
Pubmed: PMID:12124399   (View Abstract at PubMed)
PMCID: PMC124997   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.162269099   (Journal Full-text)

The principle that developmentally silenced globin genes can be reactivated in adults with defects in beta-globin gene expression has been well established both in vitro and in vivo. In practice, levels of developmental stage-discordant fetal gamma globin that can be achieved by using currently approved therapies are generally insufficient to fully resolve typical clincopathological features of sickle cell disease. The therapeutic potential of another developmentally silenced globin--embryonic epsilon globin--has been difficult to evaluate in the absence of a convenient expression system or an appropriate experimental model. The current work analyzes the antisickling properties of an epsilon -globin-containing heterotetramer (Hb Gower-2) both in vitro as well as in vivo in a well-established mouse model of sickle cell anemia. These animals, expressing 100% human Hb S, display a chronic hemolytic anemia with compensatory marrow and extramedullary erythropoiesis, abundant circulating sickled erythrocytes, and chronic tissue damage evidenced by parallel histopathological and functional deficits. By comparison, related mice that coexpress Hb S as well as Hb Gower-2 exhibit normal physiological, morphological, histological, and functional attributes. Subsequent in vitro analyses substantiate results from whole-animal studies, indicating that the polymerization of deoxygenated Hb S can be significantly slowed by relatively small quantities of Hb Gower-2. Together, the in vivo and in vitro analyses suggest that reactivation of epsilon-globin gene expression would be therapeutically beneficial to adults with sickle phenotypes, and provide a rationale for detailed investigations into the molecular basis for its developmental silencing.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HBE1Humansickle cell anemia treatmentIMP  RGD 
Hbb-yMousesickle cell anemia treatmentISOHBE1 (Homo sapiens) RGD 
Hbe1Ratsickle cell anemia treatmentISOHBE1 (Homo sapiens) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hbe1  (hemoglobin subunit epsilon 1)

Genes (Mus musculus)
Hbb-y  (hemoglobin Y, beta-like embryonic chain)

Genes (Homo sapiens)
HBE1  (hemoglobin subunit epsilon 1)


Additional Information