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Papers In Press, published online ahead of print August 29, 2001
J. Biol. Chem, 10.1074/jbc.M105844200
Submitted on June 22, 2001
Revised on August 7, 2001
Accepted on August 29, 2001
Department o fPediatrics, Yale University School of Medicine, New Haven, CT 06520-8064
Corresponding Author: patrick.gallagher{at}yale.edu
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-C and -108T-C in cis with -153G-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 4 lines expressed significantly lower levels of Agamma-globin mRNA than wild type. Two of 4 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 due to HS-related, ankyrin gene promoter mutations.
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