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Originally published In Press as doi:10.1074/jbc.M105844200 on August 29, 2001

J. Biol. Chem., Vol. 276, Issue 45, 41683-41689, November 9, 2001
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Erythrocyte Ankyrin Promoter Mutations Associated with Recessive Hereditary Spherocytosis Cause Significant Abnormalities in Ankyrin Expression*

Patrick G. GallagherDagger §, Denise E. Sabatino||, Daniela S. Basseres**, Douglas M. Nilson, Clara WongDagger , Amanda P. Cline, Lisa J. Garrett, and David M. Bodine

From the Dagger  Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520, the  Hematopoiesis Section, Genetics and Molecular Biology Branch, NHGRI, National Institutes of Health, Bethesda, Maryland 20892, and ** Hemocentro, University of Campinas, Campinas, Brazil

Ankyrin defects are the most common cause of hereditary spherocytosis (HS). In several kindreds with recessive, ankyrin-deficient HS, mutations have been identified in the ankyrin promoter that have been proposed to decrease ankyrin synthesis. We analyzed the effects of two mutations, -108T to C and -108T to C in cis with -153G to A, on ankyrin expression. No difference between wild type and mutant promoters was demonstrated in transfection or gel shift assays in vitro. Transgenic mice with a wild type ankyrin promoter linked to a human Agamma -globin gene expressed gamma -globin in 100% of erythrocytes in a copy number-dependent, position-independent manner. Transgenic mice with the mutant -108 promoter demonstrated variegated gamma -globin expression, but showed copy number-dependent and position-independent expression similar to wild type. Severe effects in ankyrin expression were seen in mice with the linked -108/-153 mutations. Three transgenic lines had undetectable levels of Agamma -globin mRNA, indicating position-dependent expression, and four lines expressed significantly lower levels of Agamma -globin mRNA than wild type. Two of four expressing lines showed variegated gamma -globin expression, and there was no correlation between transgene copy number and RNA level, indicating copy number-independent expression. These data are the first demonstration of functional defects caused by HS-related, ankyrin gene promoter mutations.

* This work was supported in part by grants from the NHLBI, National Institutes of Health (to P. G. G.) and the March of Dimes Birth Defects Foundation (to P. G. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Dept. of Pediatrics, Yale University School of Medicine, 333 Cedar St., P. O. Box 208064, New Haven, CT 06520-8064. Tel.: 203-688-2896; Fax: 203-785-6974; E-mail: patrick.gallagher@yale.edu.

|| Current address: Div. of Hematology, Dept. of Pediatrics, Children's Hospital, Philadelphia, PA 19104.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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