A Common Human β Globin Splicing Mutation Modeled in Mice

• DOI: 10.1182/blood.v91.6.2152
• Publication Date: 2019-10-14T09:22:23Z
• Authors: Jada Lewis; Baoli Yang; Ronald Kim; Halina Sierakowska; Ryszard Kole; Oliver Smithies; Nobuyo Maeda
• Keywords: Gene targeting

Abstract The βIVS-2-654 C→T mutation accounts for approximately 20% of β thalassemia mutations in southern China; it causes aberrant RNA splicing and leads to β0 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 cells to replace the two (cis) murine adult β globin genes with a single copy of the human βIVS-2-654 gene. No homozygous mice survive postnatally. Heterozygous mice carrying this mutant gene produce reduced amounts of the mouse β globin chains and no human β globin, and have a moderate form of β thalassemia. The heterozygotes show the same aberrant splicing as their human counterparts and provide an animal model for testing therapies to correct splicing defects at either the RNA or DNA level.