A COMMON HUMAN BETA-GLOBIN SPLICING MUTATION MODELED IN MICE

The beta lVS-2-654 C-->T mutation accounts for approximately 20% of be ta thalassemia mutations in southern China; it causes aberrant RNA spl icing and leads to beta(0) thalassemia. To provide an animal model for testing therapies for correcting splicing defects, we have used the ' 'plug and socket'' method of gene targeting in murine embryonic stem c ells to replace the two (cis) murine adult beta globin genes with a si ngle copy of the human beta lVS-2-654 gene. No homozygous mice survive postnatally. Heterozygous mice carrying this mutant gene produce redu ced amounts of the mouse beta globin chains and no human beta globin, and have a moderate form of beta thalassemia. The heterozygotes show t he same aberrant splicing as their human counterparts and provide an a nimal model for testing therapies to correct splicing defects at eithe r the RNA or DNA level. (C) 1998 by The American Society of Hematology .