A humanized BAC transgenic/knockout mouse model for HbE/beta-thalassemia.
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.
Jamsai
Duangporn
D
Cell and Gene Therapy Research Group, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia. duangporn.jamsai@med.monash.edu.au
Zaibak
Faten
F
Vadolas
Jim
J
Voullaire
Lucille
L
Fowler
Kerry J
KJ
Gazeas
Sophie
S
Peters
Heidi
H
Fucharoen
Suthat
S
Williamson
Robert
R
Ioannou
Panayiotis A
PA
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
D006446:Hemoglobin E