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Type: Artigo de periódico
Title: Erythrocyte ankyrin promoter mutations associated with recessive hereditary spherocytosis cause significant abnormalities in ankyrin expression
Author: Gallagher, PG
Sabatino, DE
Basseres, DS
Nilson, DM
Wong, C
Cline, AP
Garrett, LJ
Bodine, DM
Abstract: 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)gamma -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 (A)gamma -globin mRNA, indicating position-dependent expression, and four lines expressed significantly lower levels of (A)gamma -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.
Country: EUA
Editor: Amer Soc Biochemistry Molecular Biology Inc
Citation: Journal Of Biological Chemistry. Amer Soc Biochemistry Molecular Biology Inc, v. 276, n. 45, n. 41683, n. 41689, 2001.
Rights: fechado
Identifier DOI: 10.1074/jbc.M105844200
Date Issue: 2001
Appears in Collections:Unicamp - Artigos e Outros Documentos

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