A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia.
The congenital dyserythropoietic anemias (CDAs) are inherited red blood cell disorders whose hallmarks are ineffective erythropoiesis, hemolysis, and morphological abnormalities of erythroblasts in bone marrow. We have identified a missense mutation in KLF1 of patients with a hitherto unclassified CDA. KLF1 is an erythroid transcription factor, and extensive studies in mouse models have shown that it plays a critical role in the expression of globin genes, but also in the expression of a wide spectrum of genes potentially essential for erythropoiesis. The unique features of this CDA confirm the key role of KLF1 during human erythroid differentiation. Furthermore, we show that the mutation has a dominant-negative effect on KLF1 transcriptional activity and unexpectedly abolishes the expression of the water channel AQP1 and the adhesion molecule CD44. Thus, the study of this disease-causing mutation in KLF1 provides further insights into the roles of this transcription factor during erythropoiesis in humans.
National Institute of Blood Transfusion, Paris, France. larnaud@ints.fr
Lionel
L
Arnaud
Carole
C
Saison
Virginie
V
Helias
Nicole
N
Lucien
Dominique
D
Steschenko
Marie-Catherine
MC
Giarratana
Claude
C
Prehu
Bernard
B
Foliguet
Lory
L
Montout
Alexandre G
AG
de Brevern
Alain
A
Francina
Pierre
P
Ripoche
Odile
O
Fenneteau
Lydie
L
Da Costa
Thierry
T
Peyrard
Gail
G
Coghlan
Niels
N
Illum
Henrik
H
Birgens
Hannah
H
Tamary
Achille
A
Iolascon
Jean
J
Delaunay
Gil
G
Tchernia
Jean-Pierre
JP
Cartron
D000742:Anemia, Dyserythropoietic, Congenital / Q000235:genetics*; D001483:Base Sequence; D002454:Cell Differentiation; D004900:Erythroblasts; D004920:Erythropoiesis / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D009154:Mutation
D051741:Kruppel-Like Transcription Factors; C080774:erythroid Kruppel-like factor