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J. Biol. Chem., Vol. 281, Issue 11, 7399-7405, March 17, 2006

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Humanized -Thalassemia Mouse Model Containing the Common IVSI-110 Splicing Mutation^*

Jim Vadolas, Recipient of the Cooley's Anemia Research Fellowship¹, Mikhail Nefedov, Hady Wardan, Sima Mansooriderakshan, Lucille Voullaire, Duangporn Jamsai, Robert Williamson, and Panayiotis A. Ioannou

From the Cell and Gene Therapy Research Group, Murdoch Childrens Research Institute, The University of Melbourne, Royal Children's Hospital, Parkville 3052, Melbourne, Australia and The Cyprus Institute of Neurology and Genetics, P. O. Box 3462, 1683 Nicosia, Cyprus

Splicing mutations are common causes of -thalassemia. Some splicing mutations permit normal splicing as well as aberrant splicing, which can give a reduced level of normal -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 -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 -globin (^hu-globin) locus. We examined heterozygous murine -globin knock-out mice (^muth-3/+) carrying either the IVSI-110 or the normal ^hu-globin locus. Our results show a 90% decrease in ^hu-globin chain synthesis in the IVSI-110 mouse model compared with the mouse model carrying the normal ^hu-globin locus. This notable difference is attributed to aberrant splicing. The humanized IVSI-110 mouse model accurately recapitulates the splicing defect found in comparable -thalassemia patients. This mouse model is available as a platform for testing strategies for the restoration of normal splicing.

Received for publication, December 5, 2005 , and in revised form, January 17, 2006.

^* This work was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia, the Brockhoff Foundation, the Ronald Geoffrey Arnott Foundation, and the Thalassemia Society of Victoria, Australia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Panayiotis A. Ioannou died in April 2005. This work was inspired by and led by him, and his colleagues dedicate this research to his memory.

¹ To whom correspondence should be addressed. Tel.: 613-8341-6233; Fax: 613-8341-6212; E-mail: jim.vadolas{at}mcri.edu.au.

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