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|Type:||Artigo de periódico|
|Title:||Erythrocyte ankyrin promoter mutations associated with recessive hereditary spherocytosis cause significant abnormalities in ankyrin expression|
|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.|
|Editor:||Amer Soc Biochemistry Molecular Biology Inc|
|Appears in Collections:||Unicamp - Artigos e Outros Documentos|
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