title: A humanized BAC transgenic/knockout mouse model for HbE/beta-thalassemia.
abstract: Hemoglobin E (HbE) is caused by a G-->A mutation at codon 26 of the beta-globin gene, which substitutes Glu-->Lys. This mutation gives rise to functional but unstable hemoglobin and activates a cryptic splice site causing mild anemia. HbE reaches a carrier frequency of 60-80% in some Southeast Asian populations. HbE causes serious disease when co-inherited with a beta-thalassemia mutation. In this study, we report the creation and evaluation of humanized transgenic mice containing the beta(E) mutation in the context of the human beta-globin locus. Developmental expression of the human beta(E) locus transgene partially complements the hematological abnormalities in heterozygous knockout mice ((mu)beta(th-3/+)) and rescues the embryonic lethality of homozygous knockout mice ((mu)beta(th-3/th-3)). The phenotype of rescued mice was dependent on the transgene copy number. This mouse model displays hematological abnormalities similar to HbE/beta-thalassemia patients and represent an ideal in vivo model system for pathophysiological studies and evaluation of novel therapies.
authors.affiliation: Cell and Gene Therapy Research Group, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia. duangporn.jamsai@med.monash.edu.au
authors.forename: Duangporn
authors.initials: D
authors.lastname: Jamsai
authors.forename: Faten
authors.initials: F
authors.lastname: Zaibak
authors.forename: Jim
authors.initials: J
authors.lastname: Vadolas
authors.forename: Lucille
authors.initials: L
authors.lastname: Voullaire
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Fowler
authors.forename: Sophie
authors.initials: S
authors.lastname: Gazeas
authors.forename: Heidi
authors.initials: H
authors.lastname: Peters
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.forename: Robert
authors.initials: R
authors.lastname: Williamson
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Ioannou
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018628:Gene Dosage; D006446:Hemoglobin E / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D017354:Point Mutation; D019076:Transgenes; D017086:beta-Thalassemia / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: D006446:Hemoglobin E