A 191-kb genomic fragment containing the human α-globin locus can rescue α-thalassemic mice

Keith Al-Hasani, Jim Vadolas, Anja S. Knaupp, Hady Wardan, Lucille Voullaire, Robert Williamson, Panayiotis A. Ioannou

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6 Citations (Scopus)

Abstract

A 191-kb human bacterial artificial chromosome (BAC) containing the human α-globin genomic locus was used to generate transgenic mice that express, exclusively, human α-globin (huα-globin). Expression of huα-globin reaches a level of 36% of that of endogenous mouse α-globin (muα-globin) on a heterozygous mouse α-thalassemia background (muα-globin knockout, muα+/-). Hemizygous transgenic mice carrying the huα-globin locus on a heterozygous knockout background ( huα+/0, muα++/ -) demonstrated complementation of most hematologic parameters. By crossing huα+/0, muα++/ - mice, we were able to generate mice entirely dependent on huα-globin synthesis. Breeding and fluorescent in situ hybridization studies demonstrate that only mice homozygous for the transgene were able to rescue embryonic lethal homozygous muα-globin knockout embryos (muα - / -). Adult rescued mice produce hemoglobin at levels similar to wild-type mice, with partial red cell complementation based on mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and red cell distribution width (RDW) measurements. Significant erythrocythemia above wild-type levels seems to be the main compensatory mechanism for the normalization of the hemoglobin levels in the rescued animals. Our studies demonstrate that the huα-globin locus in the 191-kb transgene contains all the necessary elements for the regulated expression of huα-globin in transgenic mice. This animal model should be valuable for studying the mechanisms regulating huα-globin production and for development of therapeutic strategies for β-thalassemia based on downregulation of α-globin expression.

Original languageEnglish
Pages (from-to)847-853
Number of pages7
JournalMammalian Genome
Volume16
Issue number11
DOIs
Publication statusPublished - 1 Nov 2005

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