|
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
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.
*
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.

CiteULike Complore Connotea Del.icio.us Digg Reddit Technorati What's this?
This article has been cited by other articles:

|
 |

|
 |
 
P. G. Gallagher, D. G. Nilson, L. A. Steiner, Y. D. Maksimova, J. Y. Lin, and D. M. Bodine
An insulator with barrier-element activity promotes {alpha}-spectrin gene expression in erythroid cells
Blood,
February 12, 2009;
113(7):
1547 - 1554.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Mariani, W. Barcellini, C. Vercellati, A. P. Marcello, E. Fermo, P. Pedotti, C. Boschetti, and A. Zanella
Clinical and hematologic features of 300 patients affected by hereditary spherocytosis grouped according to the type of the membrane protein defect
Haematologica,
September 1, 2008;
93(9):
1310 - 1317.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
P. G. Gallagher, R. I. Liem, E. Wong, M. J. Weiss, and D. M. Bodine
GATA-1 and Oct-1 Are Required for Expression of the Human {alpha}-Hemoglobin-stabilizing Protein Gene
J. Biol. Chem.,
November 25, 2005;
280(47):
39016 - 39023.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
P. G. Gallagher, D. G. Nilson, C. Wong, J. L. Weisbein, L. J. Garrett-Beal, S. W. Eber, and D. M. Bodine
A dinucleotide deletion in the ankyrin promoter alters gene expression, transcription initiation and TFIID complex formation in hereditary spherocytosis
Hum. Mol. Genet.,
September 1, 2005;
14(17):
2501 - 2509.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. F. Frazar, J. L. Weisbein, S. M. Anderson, A. P. Cline, L. J. Garrett, G. Felsenfeld, P. G. Gallagher, and D. M. Bodine
Variegated Expression from the Murine Band 3 (AE1) Promoter in Transgenic Mice Is Associated with mRNA Transcript Initiation at Upstream Start Sites and Can Be Suppressed by the Addition of the Chicken {beta}-Globin 5' HS4 Insulator Element
Mol. Cell. Biol.,
July 15, 2003;
23(14):
4753 - 4763.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. A. Persons, P. W. Hargrove, E. R. Allay, H. Hanawa, and A. W. Nienhuis
The degree of phenotypic correction of murine beta -thalassemia intermedia following lentiviral-mediated transfer of a human gamma -globin gene is influenced by chromosomal position effects and vector copy number
Blood,
March 15, 2003;
101(6):
2175 - 2183.
[Abstract]
[Full Text]
[PDF]
|
 |
|
Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.
|
Advertisement
Advertisement
|