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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. Gallagher^§, Denise E. Sabatino^¶, Daniela S. Basseres^**, Douglas M. Nilson^¶, Clara Wong, Amanda P. Cline^¶, Lisa J. Garrett^¶, and David M. Bodine^¶

From the  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 ^A-globin gene expressed -globin in 100% of erythrocytes in a copy number-dependent, position-independent manner. Transgenic mice with the mutant 108 promoter demonstrated variegated -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 ^A-globin mRNA, indicating position-dependent expression, and four lines expressed significantly lower levels of ^A-globin mRNA than wild type. Two of four expressing lines showed variegated -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.

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