These authors contributed equally to this study.
Molecular Analysis of the Rare In(Lu) Blood Type: Toward Decoding the Phenotypic Outcome of Haploinsufficiency for the Transcription Factor KLF1
Article first published online: 2 NOV 2012
© 2012 WILEY PERIODICALS, INC.
Volume 34, Issue 1, pages 221–228, January 2013
How to Cite
Helias, V., Saison, C., Peyrard, T., Vera, E., Prehu, C., Cartron, J.-P. and Arnaud, L. (2013), Molecular Analysis of the Rare In(Lu) Blood Type: Toward Decoding the Phenotypic Outcome of Haploinsufficiency for the Transcription Factor KLF1. Hum. Mutat., 34: 221–228. doi: 10.1002/humu.22218
Contract grant sponsors: National Institute of Blood Transfusion (INTS); National Institute for Health and Medical Research (INSERM); Paris Diderot University (Paris 7).
Communicated by Sergio Ottolenghi
- Issue published online: 20 DEC 2012
- Article first published online: 2 NOV 2012
- Accepted manuscript online: 3 OCT 2012 03:35AM EST
- Manuscript Accepted: 30 AUG 2012
- Manuscript Received: 2 JUN 2012
- National Institute of Blood Transfusion (INTS)
- National Institute for Health and Medical Research (INSERM)
- Paris Diderot University (Paris 7)
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 HbA2 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.