title: Molecular analysis of the rare in(Lu) blood type: toward decoding the phenotypic outcome of haploinsufficiency for the transcription factor KLF1.
abstract: KLF1 encodes an erythroid transcription factor, whose essential function in erythropoiesis has been demonstrated by extensive studies in mouse models. The first reported mutations in human KLF1 were found in individuals with a rare and asymptomatic blood type called In(Lu). Here, we show that KLF1 haploinsufficiency is responsible for the In(Lu) blood type, after redefining this peculiar blood type using flow cytometry to quantify the levels of BCAM and CD44 on red blood cells. We found 10 (seven novel) heterozygous KLF1 mutations responsible for the In(Lu) blood type. Although most were obligate loss-of-function mutations due to the truncation of the DNA-binding domain of KLF1, three were missense mutations that were located in its DNA-binding domain and impaired the transactivation capacity of KLF1 in vitro. We further showed that the levels of the hemoglobin variants HbF and HbA(2)  were increased in the In(Lu) blood type, albeit differently. The levels of the membrane glycoproteins BCAM and CD44 were also differently reduced on In(Lu) red blood cells. This biochemical and genetic analysis of the In(Lu) blood type tackles the phenotypic outcome of haploinsufficiency for a transcription factor.
authors.affiliation: National Institute of Blood Transfusion, INTS, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Helias
authors.forename: Carole
authors.initials: C
authors.lastname: Saison
authors.forename: Thierry
authors.initials: T
authors.lastname: Peyrard
authors.forename: Eliane
authors.initials: E
authors.lastname: Vera
authors.forename: Claude
authors.initials: C
authors.lastname: Prehu
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Cartron
authors.forename: Lionel
authors.initials: L
authors.lastname: Arnaud
mesh_terms: D000818:Animals; D001789:Blood Group Antigens / Q000235:genetics*; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000097:blood / Q000235:genetics; D002522:Chlorocebus aethiops; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D005915:Globosides / Q000235:genetics; D057895:Haploinsufficiency; D006443:Hemoglobin A2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000097:blood; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008188:Lutheran Blood-Group System / Q000097:blood / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics; D012097:Repressor Proteins
chemical_list: C090228:BCAM protein, human; C486563:BCL11A protein, human; D001789:Blood Group Antigens; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D005915:Globosides; D018960:Hyaluronan Receptors; D051741:Kruppel-Like Transcription Factors; D008188:Lutheran Blood-Group System; D009687:Nuclear Proteins; D020598:Proto-Oncogene Proteins c-myb; D012097:Repressor Proteins; C080774:erythroid Kruppel-like factor; C480041:galactopyranosyl-1-4-paragloboside; D006443:Hemoglobin A2; D005319:Fetal Hemoglobin