Humanized β-thalassemia mouse model containing the common IVSI-110 splicing mutation

Jim Vadolas, Mikhail Nefedov, Hady Wardan, Sima Mansooriderakshan, Lucille Voullaire, Duangporn Jamsai, Robert Williamson, Panayiotis A Ioannou

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31 Citations (Scopus)


Splicing mutations are common causes of beta-thalassemia. Some splicing mutations permit normal splicing as well as aberrant splicing, which can give a reduced level of normal beta-globin synthesis causing mild disease (thalassemia intermedia). For other mutations, normal splicing is reduced to low levels, and patients are transfusion-dependent when homozygous for the disease. The development of therapies for beta-thalassemia will require suitable mouse models for preclinical studies. In this study, we report the generation of a humanized mouse model carrying the common IVSI-110 splicing mutation on a BAC including the human beta-globin ((hu)beta-globin) locus. We examined heterozygous murine beta-globin knock-out mice ((mu)beta(th-3/+)) carrying either the IVSI-110 or the normal (hu)beta-globin locus. Our results show a 90 decrease in (hu)beta-globin chain synthesis in the IVSI-110 mouse model compared with the mouse model carrying the normal (hu)beta-globin locus. This notable difference is attributed to aberrant splicing. The humanized IVSI-110 mouse model accurately recapitulates the splicing defect found in comparable beta-thalassemia patients. This mouse model is available as a platform for testing strategies for the restoration of normal splicing.
Original languageEnglish
Pages (from-to)7399 - 7405
Number of pages7
JournalJournal of Biological Chemistry
Issue number11
Publication statusPublished - 2006
Externally publishedYes

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